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[[File:Pseudomonas aeruginosa Gram.jpg|thumb|Microscopic image of gram-negative ''[[Pseudomonas aeruginosa]]'' bacteria (pink-red rods)]]<!--no px size to allow auto-sizing per user-->
[[File:Pseudomonas aeruginosa Gram.jpg|thumb|Microscopic image of gram-negative ''[[Pseudomonas aeruginosa]]'' bacteria (pink-red rods)]]<!--no px size to allow auto-sizing per user-->


'''Gram-negative bacteria''' are [[bacteria]] that, unlike [[gram-positive bacteria]], do not retain the [[Crystal violet|crystal violet stain]] used in the [[Gram stain]]ing method of bacterial differentiation.<ref name=Baron>{{cite book| pmid = 21413343| vauthors = Baron S, Salton MR, Kim KS| chapter = Structure| title = Medical Microbiology| editor = Baron S| edition = 4th| publisher = University of Texas Medical Branch at Galveston| year = 1996| chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK8477/| isbn = 978-0-9631172-1-2| access-date = 2021-08-18| archive-date = 2021-07-06| archive-url = https://web.archive.org/web/20210706013613/https://www.ncbi.nlm.nih.gov/books/NBK8477/| url-status = live}}</ref> Their defining characteristic is that their [[cell envelope]] consists of a thin [[peptidoglycan]] [[gram-negative cell wall|cell wall]] sandwiched between an inner ([[Cytoplasm|cytoplasmic]]) [[Cell membrane|membrane]] and an [[Bacterial outer membrane|outer membrane]].<ref>{{Cite journal |last1=Silhavy |first1=T. J. |last2=Kahne |first2=D. |last3=Walker |first3=S. |date=2010-05-01 |title=The Bacterial Cell Envelope |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=2 |issue=5 |pages=a000414 |doi=10.1101/cshperspect.a000414 |issn=1943-0264 |pmc=2857177 |pmid=20452953}}</ref> These bacteria are found in all environments that support life on [[Earth]].
'''Gram-negative bacteria''' are [[bacteria]] that, unlike [[gram-positive bacteria]], do not retain the [[Crystal violet|crystal violet stain]] used in the [[Gram stain]]ing method of bacterial differentiation.<ref name=Baron>{{cite book| pmid = 21413343| vauthors = Baron S, Salton MR, Kim KS| chapter = Structure| title = Medical Microbiology| editor = Baron S| edition = 4th| publisher = University of Texas Medical Branch at Galveston| year = 1996| chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK8477/| isbn = 978-0-9631172-1-2| access-date = 2021-08-18| archive-date = 2021-07-06| archive-url = https://web.archive.org/web/20210706013613/https://www.ncbi.nlm.nih.gov/books/NBK8477/| url-status = live}}</ref> Their defining characteristic is that their [[cell envelope]] consists of a thin [[peptidoglycan]] [[gram-negative cell wall|cell wall]] sandwiched between an inner ([[cytoplasm]]ic) [[Cell membrane|membrane]] and an [[Bacterial outer membrane|outer membrane]].<ref>{{Cite journal |last1=Silhavy |first1=T. J. |last2=Kahne |first2=D. |last3=Walker |first3=S. |date=2010-05-01 |title=The Bacterial Cell Envelope |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=2 |issue=5 |article-number=a000414 |doi=10.1101/cshperspect.a000414 |issn=1943-0264 |pmc=2857177 |pmid=20452953}}</ref> These bacteria are found in all environments that support life on [[Earth]].


Within this category, notable species include the [[model organism]] ''[[Escherichia coli]]'', along with various [[pathogenic bacteria]], such as ''[[Pseudomonas aeruginosa]]'', ''[[Chlamydia trachomatis]]'', and ''[[Yersinia pestis]]''. They pose significant challenges in the medical field due to their outer membrane, which acts as a protective barrier against numerous [[Antibiotic|antibiotics]] (including [[penicillin]]), [[Detergent|detergents]] that would normally damage the inner cell membrane, and the [[antimicrobial]] enzyme [[lysozyme]] produced by animals as part of their [[innate immune system]]. Furthermore, the outer [[Lipid_bilayer|leaflet]] of this membrane contains a complex [[lipopolysaccharide]] (LPS) whose [[lipid A]] component can trigger a toxic reaction when the bacteria are [[Lysis|lysed]] by immune cells. This reaction may lead to [[septic shock]], resulting in [[hypotension|low blood pressure]], [[respiratory failure]], [[hypoxia (medical)|reduced oxygen delivery]], and [[lactic acidosis]].<ref name="ww.ncbi.nlm.nih.gov">{{cite book |pmid=21413321 |last1=Pelletier |first1=Lawrence L. |editor=Baron S |title=Medical Microbiology |date=1996 |publisher=University of Texas Medical Branch at Galveston |isbn=978-0-9631172-1-2 |edition=4th |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK8290/ |chapter=Microbiology of the Circulatory System |access-date=2021-05-12 |archive-date=2022-04-13 |archive-url=https://web.archive.org/web/20220413142416/https://www.ncbi.nlm.nih.gov/books/NBK8290/ |url-status=live }}</ref>
Within this category, notable species include the [[model organism]] ''[[Escherichia coli]]'', along with various [[pathogenic bacteria]], such as ''[[Pseudomonas aeruginosa]]'', ''[[Chlamydia trachomatis]]'', and ''[[Yersinia pestis]]''. They pose significant challenges in the medical field due to their outer membrane, which acts as a protective barrier against numerous [[antibiotic]]s (including [[penicillin]]), [[detergent]]s that would normally damage the inner cell membrane, and the [[antimicrobial]] enzyme [[lysozyme]] produced by animals as part of their [[innate immune system]]. Furthermore, the outer [[Lipid bilayer|leaflet]] of this membrane contains a complex [[lipopolysaccharide]] (LPS) whose [[lipid A]] component can trigger a toxic reaction when the bacteria are [[Lysis|lysed]] by immune cells. This reaction may lead to [[septic shock]], resulting in [[hypotension|low blood pressure]], [[respiratory failure]], [[hypoxia (medical)|reduced oxygen delivery]], and [[lactic acidosis]].<ref name="ww.ncbi.nlm.nih.gov">{{cite book |pmid=21413321 |last1=Pelletier |first1=Lawrence L. |editor=Baron S |title=Medical Microbiology |date=1996 |publisher=University of Texas Medical Branch at Galveston |isbn=978-0-9631172-1-2 |edition=4th |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK8290/ |chapter=Microbiology of the Circulatory System |access-date=2021-05-12 |archive-date=2022-04-13 |archive-url=https://web.archive.org/web/20220413142416/https://www.ncbi.nlm.nih.gov/books/NBK8290/ |url-status=live }}</ref>


Several [[Antibiotics#Classes|classes of antibiotic]]s have been developed to target gram-negative bacteria, including [[aminopenicillin]]s, [[ureidopenicillin]]s, [[cephalosporin]]s, [[beta-lactam]]-[[Β-Lactamase inhibitor|betalactamase inhibitor]] combinations (such as [[Piperacillin/tazobactam|piperacillin-tazobactam]]), [[Antifolate|folate antagonist]]s, [[quinolone antibiotic|quinolones]], and [[carbapenem]]s. Many of these antibiotics also cover gram-positive bacteria. The antibiotics that specifically target gram-negative organisms include [[aminoglycoside]]s, [[monobactam]]s (such as [[aztreonam]]), and [[ciprofloxacin]].
Several [[Antibiotics#Classes|classes of antibiotic]]s have been developed to target gram-negative bacteria, including [[aminopenicillin]]s, [[ureidopenicillin]]s, [[cephalosporin]]s, [[beta-lactam]]-[[Β-Lactamase inhibitor|betalactamase inhibitor]] combinations (such as [[Piperacillin/tazobactam|piperacillin-tazobactam]]), [[Antifolate|folate antagonist]]s, [[quinolone antibiotic|quinolones]], and [[carbapenem]]s. Many of these antibiotics also cover gram-positive bacteria. The antibiotics that specifically target gram-negative bacteria include [[aminoglycoside]]s, [[monobactam]]s (such as [[aztreonam]]), and [[ciprofloxacin]].


== Characteristics ==
== Characteristics ==
[[File:Gram negative cell wall.svg|thumb|500px|right|Gram-negative (LPS-diderm) [[cell wall]] structure]]
[[File:Gram negative cell wall.svg|thumb|500px|right|Gram-negative (LPS-diderm) [[cell wall]] structure]]
[[File:Gram-Cell-wall.svg|thumb|right|[[Gram-positive]] and -negative [[bacteria]] are differentiated chiefly by their [[cell wall]] structure]]
[[File:Gram-Cell-wall.svg|thumb|right|[[Gram-positive]] and gram-negative bacteria are differentiated chiefly by their [[cell wall]] structure]]


Conventional gram-negative (LPS-diderm) bacteria display {{nowrap|the following characteristics}}:{{cn|date=July 2022}}
Conventional gram-negative (LPS-diderm) bacteria display {{nowrap|the following characteristics}}:{{citation needed|date=July 2022}}
* An inner [[cell membrane]] is present ([[cytoplasm]]ic)
* An inner [[cell membrane]] is present ([[cytoplasm]]ic)
* A thin [[peptidoglycan]] layer is present (this is much thicker in gram-positive bacteria)
* A thin [[peptidoglycan]] layer is present (this is much thicker in gram-positive bacteria)
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Since 1987, the [[monophyly]] of the gram-negative bacteria has been [[Proof (truth)|disproven]] with [[Molecular phylogenetics|molecular studies]].<ref name="woese87">{{cite journal | author = Woese CR | title = Bacterial evolution | journal = Microbiol. Rev. | volume = 51 | issue = 2 | pages = 221–71 |date=June 1987 | pmid = 2439888 | pmc = 373105 | doi =  10.1128/MMBR.51.2.221-271.1987}}</ref>
Since 1987, the [[monophyly]] of the gram-negative bacteria has been [[Proof (truth)|disproven]] with [[Molecular phylogenetics|molecular studies]].<ref name="woese87">{{cite journal | author = Woese CR | title = Bacterial evolution | journal = Microbiol. Rev. | volume = 51 | issue = 2 | pages = 221–71 |date=June 1987 | pmid = 2439888 | pmc = 373105 | doi =  10.1128/MMBR.51.2.221-271.1987}}</ref>


Current knowledge divides the gram-negatives into two large groups and some straddlers. The more "conventional" gram-negatives with an LPS outer membrane do share a common ancestor and are grouped in kingdom [[Pseudomonadati]].<ref name="valid-dom-kingdom"/> The less conventional ones are, as mentioned above, the order [[Mycobacteriales]], have a [[mycolic acid]] cell wall and an outer membrane.<ref name=Gupta19myc/> The kingdom and the order are each monophyletic (or rather, not holyphyletic), but the "LPS-diderm" and "mycolic-diderm" groups are not, because some bacteria in the kingdom and the order do not, in fact, stain gram negative. They will be discussed in the next section.
Current knowledge divides the gram-negative bacteri into two large groups and some straddlers. The more "conventional" with an LPS outer membrane do share a common ancestor and are grouped in kingdom [[Pseudomonadati]].<ref name="valid-dom-kingdom"/> The less conventional ones are the order [[Mycobacteriales]], that have a [[mycolic acid]] cell wall and an outer membrane.<ref name=Gupta19myc/> The kingdom and the order are each monophyletic (or rather, not holyphyletic), but the "LPS-diderm" and "mycolic-diderm" groups are not, because some bacteria in the kingdom and the order do not stain gram negative. They will be discussed in the next section.


== Taxonomy ==
== Taxonomy ==
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Bacteria are traditionally classified based on their [[Gram stain|Gram-staining]] response into the [[gram-positive]] and gram-negative bacteria. Having just one membrane, the gram-positive bacteria are also known as [[monoderm bacteria]], while gram-negative bacteria, having two membranes, are also known as '''diderm bacteria'''. It was traditionally thought that the groups represent lineages, i.e., the extra membrane only evolved once, such that gram-negative bacteria are more closely related to one another than to any gram-positive bacteria. While this is often true, the classification system breaks down in some cases, with lineage groupings not matching the staining result.<ref name="Guptab">{{cite journal|last=Gupta |first=RS |title=Protein phylogenies and signature sequences: A reappraisal of evolutionary relationships among archaebacteria, eubacteria, and eukaryotes |journal=Microbiol. Mol. Biol. Rev. |volume=62 |issue=4 |pages=1435–91 |date=December 1998 |pmid=9841678 |pmc=98952 |doi=10.1128/MMBR.62.4.1435-1491.1998}}</ref><ref name="Guptad">{{cite journal | author = Gupta RS | title = The natural evolutionary relationships among prokaryotes | journal = Crit. Rev. Microbiol. | volume = 26 | issue = 2 | pages = 111–31 | year = 2000 | pmid = 10890353 | doi = 10.1080/10408410091154219 | url = http://www.life.illinois.edu/govindjee/Part2/15_Gupta.pdf | citeseerx = 10.1.1.496.1356 | s2cid = 30541897 | access-date = 2017-10-24 | archive-date = 2018-07-20 | archive-url = https://web.archive.org/web/20180720153253/http://www.life.illinois.edu/govindjee/Part2/15_Gupta.pdf | url-status = live }}</ref><ref name="Desvaux et al., 2009">{{cite journal |vauthors=Desvaux M, Hébraud M, Talon R, Henderson IR | title = Secretion and subcellular localizations of bacterial proteins: a semantic awareness issue | journal = Trends Microbiol. | volume = 17 | issue = 4 | pages = 139–45 |date=April 2009 | pmid = 19299134 | doi = 10.1016/j.tim.2009.01.004 }}</ref><ref name="Sutcliffe, 2010">{{cite journal | author = Sutcliffe IC | title = A phylum level perspective on bacterial cell envelope architecture | journal = Trends Microbiol. | volume = 18 | issue = 10 | pages = 464–70 |date=October 2010 | pmid = 20637628 | doi = 10.1016/j.tim.2010.06.005 }}</ref> Thus, Gram staining cannot be reliably used to assess familial relationships of bacteria. Nevertheless, staining often gives reliable information about the composition of the cell membrane, distinguishing between the presence or absence of an [[bacterial outer membrane|outer lipid membrane]].<ref name="Guptab"/><ref name="Guptaa">{{cite journal | author = Gupta RS | title = What are archaebacteria: life's third domain or monoderm prokaryotes related to gram-positive bacteria? A new proposal for the classification of prokaryotic organisms | journal = Mol. Microbiol. | volume = 29 | issue = 3 | pages = 695–707 |date=August 1998 | pmid = 9723910 | doi = 10.1046/j.1365-2958.1998.00978.x | doi-access = free }}</ref>
Bacteria are traditionally classified based on their [[Gram stain|Gram-staining]] response into the [[gram-positive]] and gram-negative bacteria. Having just one membrane, the gram-positive bacteria are also known as [[monoderm bacteria]], while gram-negative bacteria, having two membranes, are also known as '''diderm bacteria'''. It was traditionally thought that the groups represent lineages, i.e., the extra membrane only evolved once, such that gram-negative bacteria are more closely related to one another than to any gram-positive bacteria. While this is often true, the classification system breaks down in some cases, with lineage groupings not matching the staining result.<ref name="Guptab">{{cite journal|last=Gupta |first=RS |title=Protein phylogenies and signature sequences: A reappraisal of evolutionary relationships among archaebacteria, eubacteria, and eukaryotes |journal=Microbiol. Mol. Biol. Rev. |volume=62 |issue=4 |pages=1435–91 |date=December 1998 |pmid=9841678 |pmc=98952 |doi=10.1128/MMBR.62.4.1435-1491.1998}}</ref><ref name="Guptad">{{cite journal | author = Gupta RS | title = The natural evolutionary relationships among prokaryotes | journal = Crit. Rev. Microbiol. | volume = 26 | issue = 2 | pages = 111–31 | year = 2000 | pmid = 10890353 | doi = 10.1080/10408410091154219 | url = http://www.life.illinois.edu/govindjee/Part2/15_Gupta.pdf | citeseerx = 10.1.1.496.1356 | s2cid = 30541897 | access-date = 2017-10-24 | archive-date = 2018-07-20 | archive-url = https://web.archive.org/web/20180720153253/http://www.life.illinois.edu/govindjee/Part2/15_Gupta.pdf | url-status = live }}</ref><ref name="Desvaux et al., 2009">{{cite journal |vauthors=Desvaux M, Hébraud M, Talon R, Henderson IR | title = Secretion and subcellular localizations of bacterial proteins: a semantic awareness issue | journal = Trends Microbiol. | volume = 17 | issue = 4 | pages = 139–45 |date=April 2009 | pmid = 19299134 | doi = 10.1016/j.tim.2009.01.004 }}</ref><ref name="Sutcliffe, 2010">{{cite journal | author = Sutcliffe IC | title = A phylum level perspective on bacterial cell envelope architecture | journal = Trends Microbiol. | volume = 18 | issue = 10 | pages = 464–70 |date=October 2010 | pmid = 20637628 | doi = 10.1016/j.tim.2010.06.005 }}</ref> Thus, Gram staining cannot be reliably used to assess familial relationships of bacteria. Nevertheless, staining often gives reliable information about the composition of the cell membrane, distinguishing between the presence or absence of an [[bacterial outer membrane|outer lipid membrane]].<ref name="Guptab"/><ref name="Guptaa">{{cite journal | author = Gupta RS | title = What are archaebacteria: life's third domain or monoderm prokaryotes related to gram-positive bacteria? A new proposal for the classification of prokaryotic organisms | journal = Mol. Microbiol. | volume = 29 | issue = 3 | pages = 695–707 |date=August 1998 | pmid = 9723910 | doi = 10.1046/j.1365-2958.1998.00978.x | doi-access = free }}</ref>


Of these two structurally distinct groups of [[Prokaryote|prokaryotic]] organisms, monoderm prokaryotes are thought to be ancestral. Based upon a number of different observations, including that the gram-positive bacteria are the most sensitive to [[antibiotics]] and that the gram-negative bacteria are, in general, [[antimicrobial resistance|resistant]] to antibiotics, it has been proposed that the outer cell membrane in gram-negative bacteria (diderms) evolved as a protective mechanism against antibiotic [[Evolutionary pressure|selection pressure]].<ref name="Guptab"/><ref name="Guptad"/><ref name="Guptaa"/><ref name="Guptac">{{cite journal | author = Gupta RS | title = Origin of diderm (gram-negative) bacteria: antibiotic selection pressure rather than endosymbiosis likely led to the evolution of bacterial cells with two membranes | journal = Antonie van Leeuwenhoek | volume = 100 | issue = 2 | pages = 171–82 |date=August 2011 | pmid = 21717204 | pmc = 3133647 | doi = 10.1007/s10482-011-9616-8 }}</ref> Some bacteria such as ''[[Deinococcus]]'', which stain gram-positive due to the presence of a thick [[peptidoglycan]] layer, but also possess an outer cell membrane are suggested as intermediates in the transition between monoderm (gram-positive) and diderm (gram-negative) bacteria.<ref name="Guptab"/><ref name="Guptac"/>  
Of these two structurally distinct groups of [[Prokaryote|prokaryotic]] organisms, monoderm prokaryotes are thought to be ancestral. Based upon a number of different observations, including that the gram-positive bacteria are the most sensitive to [[antibiotics]] and that the gram-negative bacteria are, in general, [[antimicrobial resistance|resistant]] to antibiotics, it has been proposed that the outer cell membrane in gram-negative bacteria (diderms) evolved as a protective mechanism against antibiotic [[Evolutionary pressure|selection pressure]].<ref name="Guptab"/><ref name="Guptad"/><ref name="Guptaa"/><ref name="Guptac">{{cite journal | author = Gupta RS | title = Origin of diderm (gram-negative) bacteria: antibiotic selection pressure rather than endosymbiosis likely led to the evolution of bacterial cells with two membranes | journal = Antonie van Leeuwenhoek | volume = 100 | issue = 2 | pages = 171–82 |date=August 2011 | pmid = 21717204 | pmc = 3133647 | doi = 10.1007/s10482-011-9616-8 }}</ref> Some bacteria such as ''[[Deinococcus]]'', which stain gram-positive due to the presence of a thick [[peptidoglycan]] layer, but also possess an outer cell membrane are suggested as intermediates in the transition between monoderm (gram-positive) and diderm (gram-negative) bacteria.<ref name="Guptab"/><ref name="Guptac"/>


The conventional LPS-''diderm'' group of gram-negative bacteria (e.g., [[Pseudomonadota]], [[Aquificota]], [[Chlamydiota]], [[Bacteroidota]], [[Chlorobiota]], "[[Cyanobacteria]]", [[Fibrobacterota]], [[Verrucomicrobiota]], [[Planctomycetota]], [[Spirochaetota]], [[Acidobacteriota]]) are uniquely identified by a few [[conserved signature indel]] (CSI) in the [[HSP60]] ([[GroEL]]) protein. The presence of this CSI in all sequenced species of conventional lipopolysaccharide-containing gram-negative bacterial phyla provides evidence that these phyla of bacteria form a [[Monophyly|monophyletic]] [[clade]] and that no loss of the outer membrane from any species from this group has occurred.<ref name="Guptac"/> They have accordingly been assigned a kingdom [[Pseudomonadati]] (formerly "Hydrobacteria").<ref name="valid-dom-kingdom"/>
The conventional LPS-''diderm'' group of gram-negative bacteria (e.g., [[Pseudomonadota]], [[Aquificota]], [[Chlamydiota]], [[Bacteroidota]], [[Chlorobiota]], [[Cyanobacteria]], [[Fibrobacterota]], [[Verrucomicrobiota]], [[Planctomycetota]], [[Spirochaetota]], [[Acidobacteriota]]) are uniquely identified by a few [[conserved signature indel]] (CSI) in the [[HSP60]] ([[GroEL]]) protein. The presence of this CSI in all sequenced species of conventional lipopolysaccharide-containing gram-negative bacterial phyla provides evidence that these phyla of bacteria form a [[Monophyly|monophyletic]] [[clade]] and that no loss of the outer membrane from any species from this group has occurred.<ref name="Guptac"/> They have accordingly been assigned a kingdom [[Pseudomonadati]] (formerly "Hydrobacteria").<ref name="valid-dom-kingdom"/>


The difficulty lies in the other taxa that also have a diderm structure.
The difficulty lies in the other taxa that also have a diderm structure.
* The first group is [[Paraphyly|paraphyletic]]. It includes a number of taxa (including [[Negativicutes]], [[Fusobacteriota]], [[Synergistota]], and [[Elusimicrobiota]]) that are either part of the [[phylum]] [[Bacillota]] (a monoderm group) or branches in its proximity.<ref name="Sutcliffe, 2010"/><ref name="Guptac"/><ref name="pmid19667386"/> They lack the [[GroEL]] CSI signature, which is proof that they do not belong in the former group.<ref name="Guptac"/> Some members are likely monoderm, just with a very thin layer of LPS to not appear on the stain. Others have more convoluted structures.<ref name="pmid39162559">{{cite journal |last1=Choi |first1=JK |last2=Poudel |first2=S |last3=Yee |first3=N |last4=Goff |first4=JL |title=Deeply branching Bacillota species exhibit atypical Gram-negative staining |journal=Microbiology Spectrum |date=3 October 2024 |volume=12 |issue=10 |pages=e0073224 |doi=10.1128/spectrum.00732-24 |pmid=39162559|pmc=11448272 }}</ref>
* The first group is [[Paraphyly|paraphyletic]]. It includes a number of taxa (including [[Negativicutes]], [[Fusobacteriota]], [[Synergistota]], and [[Elusimicrobiota]]) that are either part of the [[phylum]] [[Bacillota]] (a monoderm group) or branches in its proximity.<ref name="Sutcliffe, 2010"/><ref name="Guptac"/><ref name="pmid19667386"/> They lack the [[GroEL]] CSI signature, which is proof that they do not belong in the former group.<ref name="Guptac"/> Some members are likely monoderm, just with a very thin layer of LPS to not appear on the stain. Others have more convoluted structures.<ref name="pmid39162559">{{cite journal |last1=Choi |first1=JK |last2=Poudel |first2=S |last3=Yee |first3=N |last4=Goff |first4=JL |title=Deeply branching Bacillota species exhibit atypical Gram-negative staining |journal=Microbiology Spectrum |date=3 October 2024 |volume=12 |issue=10 |pages=e0073224 |doi=10.1128/spectrum.00732-24 |doi-access=free|pmid=39162559|pmc=11448272 }}</ref>
* The second group are the clinically-relevant ''[[Mycobacterium]]'', expanding to most of its encompassing order of [[Mycobacteriales]]. They do not have the CSI, and their cell wall is made of a different substance: [[mycolic acid]].<ref name=Gupta19myc/>
* The second group are the clinically relevant ''[[Mycobacterium]]'', expanding to most of its encompassing order of [[Mycobacteriales]]. They do not have the CSI, and their cell wall is made of a different substance: [[mycolic acid]].<ref name=Gupta19myc/>


=== Example species ===
=== Example species ===
The [[proteobacteria]] are a major superphylum of gram-negative bacteria, including ''[[Escherichia coli|E. coli]]'', ''[[Salmonella]]'', ''[[Shigella]]'', and other [[Enterobacteriaceae]], ''[[Pseudomonas]]'', ''[[Moraxella catarrhalis|Moraxella]]'', ''[[Helicobacter]]'', ''[[Stenotrophomonas]]'', ''[[Bdellovibrio]]'', [[acetic acid bacteria]], ''[[Legionella]]'' etc. Other notable groups of gram-negative bacteria include the [[cyanobacteria]], [[spirochaete]]s, and [[green sulfur bacteria]].<ref>{{Citation |last=Castenholz |first=Richard W. |title=General Characteristics of the Cyanobacteria |date=2015 |work=Bergey's Manual of Systematics of Archaea and Bacteria |pages=1–23 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118960608.cbm00019 |access-date=2025-01-25 |publisher=John Wiley & Sons, Ltd |language=en |doi=10.1002/9781118960608.cbm00019 |isbn=978-1-118-96060-8|url-access=subscription }}</ref><ref>{{Citation |last=Cole |first=John R. |title=5 - Spirochetes |date=1990-01-01 |work=Diagnostic Procedure in Veterinary Bacteriology and Mycology (Fifth Edition) |pages=41–60 |editor-last=Carter |editor-first=G. R. |url=https://linkinghub.elsevier.com/retrieve/pii/B9780121617752500098 |access-date=2025-01-25 |place=San Diego |publisher=Academic Press |doi=10.1016/b978-0-12-161775-2.50009-8 |isbn=978-0-12-161775-2 |editor2-last=Cole |editor2-first=John R.|url-access=subscription }}</ref><ref>{{Cite book |last=Schmidt |first=Thomas M. |title=Encyclopedia of Microbiology |date=2019 |publisher=Elsevier Science & Technology |isbn=978-0-12-811737-8 |edition=4th |location=San Diego |pages=527–537}}</ref>
The [[proteobacteria]] are a major superphylum of gram-negative bacteria, including ''[[Escherichia coli|E. coli]]'', ''[[Salmonella]]'', ''[[Shigella]]'', and other [[Enterobacteriaceae]], ''[[Pseudomonas]]'', ''[[Moraxella catarrhalis|Moraxella]]'', ''[[Helicobacter]]'', ''[[Stenotrophomonas]]'', ''[[Bdellovibrio]]'', [[acetic acid bacteria]], ''[[Legionella]]'' etc. Other notable groups of gram-negative bacteria include the [[cyanobacteria]], [[spirochaete]]s, and [[green sulfur bacteria]].<ref>{{Citation |last=Castenholz |first=Richard W. |title=General Characteristics of the Cyanobacteria |date=2015 |work=Bergey's Manual of Systematics of Archaea and Bacteria |pages=1–23 |url=https://onlinelibrary.wiley.com/doi/10.1002/9781118960608.cbm00019 |access-date=2025-01-25 |publisher=John Wiley & Sons, Ltd |language=en |doi=10.1002/9781118960608.cbm00019 |isbn=978-1-118-96060-8|url-access=subscription }}</ref><ref>{{Citation |last=Cole |first=John R. |title=5 - Spirochetes |date=1990-01-01 |work=Diagnostic Procedure in Veterinary Bacteriology and Mycology (Fifth Edition) |pages=41–60 |editor-last=Carter |editor-first=G. R. |url=https://linkinghub.elsevier.com/retrieve/pii/B9780121617752500098 |access-date=2025-01-25 |place=San Diego |publisher=Academic Press |doi=10.1016/b978-0-12-161775-2.50009-8 |isbn=978-0-12-161775-2 |editor2-last=Cole |editor2-first=John R.|url-access=subscription }}</ref><ref>{{Cite book |last=Schmidt |first=Thomas M. |title=Encyclopedia of Microbiology |date=2019 |publisher=Elsevier Science & Technology |isbn=978-0-12-811737-8 |edition=4th |location=San Diego |pages=527–537}}</ref>


Medically-relevant gram-negative [[diplococci]] include the four types that cause a [[sexually transmitted disease]] (''[[Neisseria gonorrhoeae]]''<ref name=Yeshanew_2018>{{cite journal |last1=Yeshanew |first1=Addisu Gize |last2=Geremew |first2=Rozina Ambachew |date=2018-07-17 |title=MNeisseria Gonorrhoae and their antimicrobial susceptibility patterns among symptomatic patients from Gondar town, north West Ethiopia |journal=Antimicrobial Resistance and Infection Control |volume=7 |issue=85 |page=85 |doi=10.1186/s13756-018-0376-3 |doi-access=free |pmid=30026943 |pmc=6050735 }}</ref>), a [[meningitis]] (''[[Neisseria meningitidis]]''<ref name="CDC 2018 y478">{{cite web | title=Vaccine Preventable Diseases Surveillance Manual | website=CDC | date=April 3, 2018 | url=https://www.cdc.gov/vaccines/pubs/surv-manual/chpt08-mening.html | access-date=January 26, 2024}}</ref>), and respiratory symptoms (''[[Moraxella catarrhalis]]'',<ref name=Verduin_2002>{{cite journal |last1=Verduin |first1=Cees M. |last2=Hol |first2=Cees |last3=Fleer |first3=Andre |last4=van Dijk |first4=Hans |last5=van Belkum |first5=Alex |date=January 2002 |title=Moraxella catarrhalis: from Emerging to Established Pathogen |journal=Clinical Microbiology Reviews |volume=15 |issue=1 |pages=125–144 |doi=10.1128/CMR.15.1.125-144.2002 |pmid=11781271 |pmc=118065 }}</ref> A [[coccobacillus]] ''[[Haemophilus influenzae]]'' is another medically relevant coccal type.<ref name="CDC 2018 b143">{{cite web | title=For Clinicians: Haemophilus influenzae | website=CDC | date=February 13, 2018 | url=https://www.cdc.gov/hi-disease/clinicians.html#:~:text=Haemophilus%20influenzae%20is%20a%20pleomorphic,that%20have%20distinct%20capsular%20polysaccharides. | access-date=January 26, 2024}}</ref>
Medically relevant gram-negative [[diplococci]] include the four types that cause a [[sexually transmitted disease]] (''[[Neisseria gonorrhoeae]]''<ref name=Yeshanew_2018>{{cite journal |last1=Yeshanew |first1=Addisu Gize |last2=Geremew |first2=Rozina Ambachew |date=2018-07-17 |title=MNeisseria Gonorrhoae and their antimicrobial susceptibility patterns among symptomatic patients from Gondar town, north West Ethiopia |journal=Antimicrobial Resistance and Infection Control |volume=7 |issue=85 |page=85 |doi=10.1186/s13756-018-0376-3 |doi-access=free |pmid=30026943 |pmc=6050735 }}</ref>), a [[meningitis]] (''[[Neisseria meningitidis]]''<ref name="CDC 2018 y478">{{cite web | title=Vaccine Preventable Diseases Surveillance Manual | website=CDC | date=April 3, 2018 | url=https://www.cdc.gov/vaccines/pubs/surv-manual/chpt08-mening.html | access-date=January 26, 2024}}</ref>), and respiratory symptoms (''[[Moraxella catarrhalis]]'',<ref name=Verduin_2002>{{cite journal |last1=Verduin |first1=Cees M. |last2=Hol |first2=Cees |last3=Fleer |first3=Andre |last4=van Dijk |first4=Hans |last5=van Belkum |first5=Alex |date=January 2002 |title=Moraxella catarrhalis: from Emerging to Established Pathogen |journal=Clinical Microbiology Reviews |volume=15 |issue=1 |pages=125–144 |doi=10.1128/CMR.15.1.125-144.2002 |pmid=11781271 |pmc=118065 }}</ref> A [[coccobacillus]] ''[[Haemophilus influenzae]]'' is another medically relevant coccal type.<ref name="CDC 2018 b143">{{cite web | title=For Clinicians: Haemophilus influenzae | website=CDC | date=February 13, 2018 | url=https://www.cdc.gov/hi-disease/clinicians.html#:~:text=Haemophilus%20influenzae%20is%20a%20pleomorphic,that%20have%20distinct%20capsular%20polysaccharides. | access-date=January 26, 2024}}</ref>


Medically relevant gram-negative [[bacillus (shape)|bacilli]] include a multitude of species. Some of them cause primarily respiratory problems (''[[Klebsiella pneumoniae]]'', ''[[Legionella pneumophila]]'', ''[[Pseudomonas aeruginosa]]''), primarily urinary problems (''[[Escherichia coli]]'', ''[[Proteus mirabilis]]'', ''[[Enterobacter cloacae]]'', ''[[Serratia marcescens]]''), and primarily gastrointestinal problems (''[[Helicobacter pylori]]'', ''[[Salmonella enteritidis]]'', ''[[Salmonella typhi]]'').{{cn|date=November 2023}}
Medically relevant gram-negative [[bacillus (shape)|bacilli]] include a multitude of species. Some of them cause primarily respiratory problems (''[[Klebsiella pneumoniae]]'', ''[[Legionella pneumophila]]'', ''[[Pseudomonas aeruginosa]]''), primarily urinary problems (''[[Escherichia coli]]'', ''[[Proteus mirabilis]]'', ''[[Enterobacter cloacae]]'', ''[[Serratia marcescens]]''), and primarily gastrointestinal problems (''[[Helicobacter pylori]]'', ''[[Salmonella enteritidis]]'', ''[[Salmonella typhi]]'').<ref name="Sherris2022">{{cite book |last1=Ryan |first1=Kenneth J. |title=Sherris Medical Microbiology |edition=8th |publisher=McGraw-Hill Education |year=2022 |isbn=978-1260464283 |chapter=18-25 |quote=Gram-negative bacilli are a diverse group of bacteria with distinct clinical niches, ranging from the respiratory tract (e.g., Pseudomonas, Legionella) to the urinary tract (e.g., E. coli, Proteus) and the gastrointestinal system (e.g., Salmonella, Helicobacter).}}</ref>


Gram-negative bacteria associated with [[hospital-acquired infection]]s include ''[[Acinetobacter baumannii]]'', which cause [[bacteremia]], secondary [[meningitis]], and [[ventilator-associated pneumonia]] in hospital [[intensive-care unit]]s.
Gram-negative bacteria associated with [[hospital-acquired infection]]s include ''[[Acinetobacter baumannii]]'', which cause [[bacteremia]], secondary [[meningitis]], and [[ventilator-associated pneumonia]] in hospital [[intensive-care unit]]s.
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[[Transformation (genetics)|Transformation]] is one of three processes for [[horizontal gene transfer]], in which exogenous genetic material passes from one [[Bacteria|bacterium]] to another, the other two being [[bacterial conjugation|conjugation]] (transfer of [[plasmid|genetic material]] between two bacterial cells in direct contact) and [[transduction (genetics)|transduction]] (injection of foreign DNA by a [[bacteriophage]] virus into the host bacterium).<ref name=Johnston>{{cite journal |vauthors=Johnston C, Martin B, Fichant G, Polard P, Claverys JP |title=Bacterial transformation: distribution, shared mechanisms and divergent control |journal=Nat. Rev. Microbiol. |volume=12 |issue=3 |pages=181–96 |year=2014 |pmid=24509783 |doi=10.1038/nrmicro3199 |s2cid=23559881 }}</ref><ref name=Korotetskiy>{{cite journal |vauthors=Korotetskiy I, Shilov S, Kuznetsova T, Kerimzhanova B, Korotetskaya N, Ivanova L, Zubenko N, Parenova R, Reva O |title=Analysis of Whole-Genome Sequences of Pathogenic Gram-Positive and Gram-Negative Isolates from the Same Hospital Environment to Investigate Common Evolutionary Trends Associated with Horizontal Gene Exchange, Mutations and DNA Methylation Patterning |journal=Microorganisms |volume=11 |issue=2 |year=2023 |page=323 |pmid=36838287 |doi=10.3390/microorganisms11020323 |doi-access=free |pmc=9961978 }}</ref> In transformation, the [[Nucleic acid|genetic material]] passes through the intervening medium, and uptake is completely dependent on the recipient bacterium.<ref name=Johnston/>
[[Transformation (genetics)|Transformation]] is one of three processes for [[horizontal gene transfer]], in which exogenous genetic material passes from one [[Bacteria|bacterium]] to another, the other two being [[bacterial conjugation|conjugation]] (transfer of [[plasmid|genetic material]] between two bacterial cells in direct contact) and [[transduction (genetics)|transduction]] (injection of foreign DNA by a [[bacteriophage]] virus into the host bacterium).<ref name=Johnston>{{cite journal |vauthors=Johnston C, Martin B, Fichant G, Polard P, Claverys JP |title=Bacterial transformation: distribution, shared mechanisms and divergent control |journal=Nat. Rev. Microbiol. |volume=12 |issue=3 |pages=181–96 |year=2014 |pmid=24509783 |doi=10.1038/nrmicro3199 |s2cid=23559881 }}</ref><ref name=Korotetskiy>{{cite journal |vauthors=Korotetskiy I, Shilov S, Kuznetsova T, Kerimzhanova B, Korotetskaya N, Ivanova L, Zubenko N, Parenova R, Reva O |title=Analysis of Whole-Genome Sequences of Pathogenic Gram-Positive and Gram-Negative Isolates from the Same Hospital Environment to Investigate Common Evolutionary Trends Associated with Horizontal Gene Exchange, Mutations and DNA Methylation Patterning |journal=Microorganisms |volume=11 |issue=2 |year=2023 |page=323 |pmid=36838287 |doi=10.3390/microorganisms11020323 |doi-access=free |pmc=9961978 }}</ref> In transformation, the [[Nucleic acid|genetic material]] passes through the intervening medium, and uptake is completely dependent on the recipient bacterium.<ref name=Johnston/>


As of 2014 about 80 species of bacteria were known to be capable of transformation, about evenly divided between [[gram-positive]] and gram-negative bacteria; the number might be an overestimate since several of the reports are supported by single papers.<ref name=Johnston/> Transformation has been studied in medically important gram-negative bacteria species such as ''[[Helicobacter pylori]]'', ''[[Legionella pneumophila]]'', ''[[Neisseria meningitidis]]'', ''[[Neisseria gonorrhoeae]]'', ''[[Haemophilus influenzae]]'' and ''[[Vibrio cholerae]]''.<ref name=Seitz>{{cite journal |vauthors=Seitz P, Blokesch M |title=Cues and regulatory pathways involved in natural competence and transformation in pathogenic and environmental Gram-negative bacteria |journal=FEMS Microbiol. Rev. |volume=37 |issue=3 |pages=336–63 |year=2013 |pmid=22928673 |doi=10.1111/j.1574-6976.2012.00353.x |doi-access=free }}</ref> It has also been studied in gram-negative species found in soil such as ''[[Pseudomonas stutzeri]]'', ''[[Acinetobacter baylyi]]'', and gram-negative plant pathogens such as ''[[Ralstonia solanacearum]]'' and ''[[Xylella fastidiosa]]''.<ref name=Seitz/>
As of 2014 about 80 species of bacteria were known to be capable of transformation, about evenly divided between gram-positive and gram-negative bacteria; the number might be an overestimate since several of the reports are supported by single papers.<ref name=Johnston/> Transformation has been studied in medically important gram-negative bacteria species such as ''[[Helicobacter pylori]]'', ''[[Legionella pneumophila]]'', ''[[Neisseria meningitidis]]'', ''[[Neisseria gonorrhoeae]]'', ''[[Haemophilus influenzae]]'' and ''[[Vibrio cholerae]]''.<ref name=Seitz>{{cite journal |vauthors=Seitz P, Blokesch M |title=Cues and regulatory pathways involved in natural competence and transformation in pathogenic and environmental Gram-negative bacteria |journal=FEMS Microbiol. Rev. |volume=37 |issue=3 |pages=336–63 |year=2013 |pmid=22928673 |doi=10.1111/j.1574-6976.2012.00353.x |doi-access=free }}</ref> It has also been studied in gram-negative species found in soil such as ''[[Pseudomonas stutzeri]]'', ''[[Acinetobacter baylyi]]'', and gram-negative plant pathogens such as ''[[Ralstonia solanacearum]]'' and ''[[Xylella fastidiosa]]''.<ref name=Seitz/>


==Role in disease==
==Role in disease==
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One of the several unique characteristics of gram-negative bacteria is the structure of the [[bacterial outer membrane]]. The outer leaflet of this membrane contains [[lipopolysaccharide]] (LPS), whose [[lipid A]] portion acts as an [[Lipopolysaccharide|endotoxin]].<ref name=Baron/> If gram-negative bacteria enter the [[circulatory system]], LPS can trigger an [[innate immune response]], activating the [[immune system]] and producing [[cytokine]]s (hormonal regulators). This leads to [[inflammation]] and can cause a toxic reaction, resulting in fever, an increased respiratory rate, and [[Hypotension|low blood pressure]]. That is why some infections with gram-negative bacteria can lead to life-threatening [[septic shock]].<ref name="ww.ncbi.nlm.nih.gov"/>
One of the several unique characteristics of gram-negative bacteria is the structure of the [[bacterial outer membrane]]. The outer leaflet of this membrane contains [[lipopolysaccharide]] (LPS), whose [[lipid A]] portion acts as an [[Lipopolysaccharide|endotoxin]].<ref name=Baron/> If gram-negative bacteria enter the [[circulatory system]], LPS can trigger an [[innate immune response]], activating the [[immune system]] and producing [[cytokine]]s (hormonal regulators). This leads to [[inflammation]] and can cause a toxic reaction, resulting in fever, an increased respiratory rate, and [[Hypotension|low blood pressure]]. That is why some infections with gram-negative bacteria can lead to life-threatening [[septic shock]].<ref name="ww.ncbi.nlm.nih.gov"/>


The outer membrane protects the bacteria from several [[antibiotic]]s, [[dye]]s, and [[detergent]]s that would normally damage either the inner membrane or the cell wall (made of [[peptidoglycan]]). The outer membrane provides these bacteria with resistance to [[lysozyme]] and [[penicillin]]. The [[Periplasm|periplasmic space]] (space between the two cell membranes) also contains [[enzyme]]s which break down or modify antibiotics. Drugs commonly used to treat gram negative infections include amino, carboxy and ureido penicillins ([[ampicillin]], [[amoxicillin]], [[Piperacillin|pipercillin]], [[ticarcillin]]). These drugs may be combined with [[beta-lactamase inhibitor]]s to combat the presence of enzymes that can digest these drugs (known as [[beta-lactamase]]s) in the peri-plasmic space. Other classes of drugs that have gram negative spectrum include [[cephalosporin]]s, [[monobactam]]s ([[aztreonam]]), [[Aminoglycoside|aminoglycosides]], [[quinolone antibiotic|quinolones]], [[macrolide]]s, [[chloramphenicol]], [[Antifolate|folate antagonists]], and [[carbapenem]]s.<ref>{{cite web|last=Glück|first=Thomas|url=https://www.jwatch.org/id200312120000007/2003/12/12/gram-negative-bacteria-and-broad-spectrum|title=Gram-Negative Bacteria and Broad-Spectrum Antibiotics: Good News Except for Fluoroquinolones|publisher=NEJM Journal Watch|website=www.jwatch.org|date=12 December 2003|access-date=10 March 2018|archive-date=10 March 2018|archive-url=https://web.archive.org/web/20180310074653/https://www.jwatch.org/id200312120000007/2003/12/12/gram-negative-bacteria-and-broad-spectrum|url-status=live}}</ref>
The outer membrane protects the bacteria from several [[antibiotic]]s, [[dye]]s, and [[detergent]]s that would normally damage either the inner membrane or the cell wall (made of [[peptidoglycan]]). The outer membrane provides these bacteria with resistance to [[lysozyme]] and [[penicillin]]. The [[Periplasm|periplasmic space]] (space between the two cell membranes) also contains [[enzyme]]s which break down or modify antibiotics. Drugs commonly used to treat Gram negative infections include amino, carboxy and ureido penicillins ([[ampicillin]], [[amoxicillin]], [[Piperacillin|pipercillin]], [[ticarcillin]]). These drugs may be combined with [[beta-lactamase inhibitor]]s to combat the presence of enzymes that can digest these drugs (known as [[beta-lactamase]]s) in the peri-plasmic space. Other classes of drugs that have Gram negative spectrum include [[cephalosporin]]s, [[monobactam]]s ([[aztreonam]]), [[aminoglycoside]]s, [[quinolone antibiotic|quinolones]], [[macrolide]]s, [[chloramphenicol]], [[Antifolate|folate antagonists]], and [[carbapenem]]s.<ref>{{cite web|last=Glück|first=Thomas|url=https://www.jwatch.org/id200312120000007/2003/12/12/gram-negative-bacteria-and-broad-spectrum|title=Gram-Negative Bacteria and Broad-Spectrum Antibiotics: Good News Except for Fluoroquinolones|publisher=NEJM Journal Watch|website=www.jwatch.org|date=12 December 2003|access-date=10 March 2018|archive-date=10 March 2018|archive-url=https://web.archive.org/web/20180310074653/https://www.jwatch.org/id200312120000007/2003/12/12/gram-negative-bacteria-and-broad-spectrum|url-status=live}}</ref>


== Orthography: capitalization ==
== Orthography: capitalization ==
<!--Please keep this text synched with that of [[Gram-positive bacteria#Orthographic note]].-->
The adjectives ''Gram-positive'' and ''Gram-negative'' derive from the surname of [[Hans Christian Gram]], a Danish bacteriologist; as [[Eponym#Orthographic conventions|eponymous adjectives]], their initial letter ''G'' can be either capital or lower-case, depending on which [[style guide]] is being adopted. For instance, the style guide of the American [[Centers for Disease Control and Prevention|CDC]] recommends writing: ''Gram stain'', ''this species is gram negative'', and ''a gram-negative species''.<ref>{{Cite web |title=''Emerging Infectious Diseases'' Journal Style Guide |url=http://wwwnc.cdc.gov/eid/pages/preferred-usage.htm |website=CDC.gov |publisher=Centers for Disease Control and Prevention}}</ref>
The adjectives ''gram-positive'' and ''gram-negative'' derive from the surname of [[Hans Christian Gram]], a Danish bacteriologist; as [[Eponym#Orthographic conventions|eponymous adjectives]], their initial letter ''G'' can be either capital or lower-case, depending on which [[style guide]] (e.g., that of the [[Centers for Disease Control and Prevention|CDC]]), if any, governs the document being written.<ref>{{cite web |publisher=Centers for Disease Control and Prevention |title=Preferred Usage - Emerging Infectious Disease journal - CDC |url=https://wwwnc.cdc.gov/eid/page/preferred-usage |work=CDC.gov |access-date=2018-03-04 |archive-date=2018-01-29 |archive-url=https://web.archive.org/web/20180129223909/https://wwwnc.cdc.gov/eid/page/preferred-usage |url-status=live }}</ref> This is further explained at ''[[Gram staining#Orthographic note|Gram staining § Orthographic note]]''.
<ref>{{cite web |publisher=Centers for Disease Control and Prevention |title=Preferred Usage - Emerging Infectious Disease journal - CDC |url=https://wwwnc.cdc.gov/eid/page/preferred-usage |work=CDC.gov |access-date=2018-03-04 |archive-date=2018-01-29 |archive-url=https://web.archive.org/web/20180129223909/https://wwwnc.cdc.gov/eid/page/preferred-usage |url-status=live }}</ref>


== See also ==
== See also ==
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== External links ==
== External links ==
* [https://web.archive.org/web/20081222045655/http://opm.phar.umich.edu:80/localization.php?localization=Bacterial%20gram-negative%20inner%20membrane 3D structures of proteins from inner membranes of Ellie Wyithe's gram-negative bacteria]
* [https://web.archive.org/web/20081222045655/http://opm.phar.umich.edu/localization.php?localization=Bacterial%20gram-negative%20inner%20membrane 3D structures of proteins from inner membranes of Ellie Wyithe's Gram-negative bacteria]


{{Bacteria}}
{{Bacteria}}

Latest revision as of 08:38, 24 May 2026

File:Pseudomonas aeruginosa Gram.jpg
Microscopic image of gram-negative Pseudomonas aeruginosa bacteria (pink-red rods)

Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation.[1] Their defining characteristic is that their cell envelope consists of a thin peptidoglycan cell wall sandwiched between an inner (cytoplasmic) membrane and an outer membrane.[2] These bacteria are found in all environments that support life on Earth.

Within this category, notable species include the model organism Escherichia coli, along with various pathogenic bacteria, such as Pseudomonas aeruginosa, Chlamydia trachomatis, and Yersinia pestis. They pose significant challenges in the medical field due to their outer membrane, which acts as a protective barrier against numerous antibiotics (including penicillin), detergents that would normally damage the inner cell membrane, and the antimicrobial enzyme lysozyme produced by animals as part of their innate immune system. Furthermore, the outer leaflet of this membrane contains a complex lipopolysaccharide (LPS) whose lipid A component can trigger a toxic reaction when the bacteria are lysed by immune cells. This reaction may lead to septic shock, resulting in low blood pressure, respiratory failure, reduced oxygen delivery, and lactic acidosis.[3]

Several classes of antibiotics have been developed to target gram-negative bacteria, including aminopenicillins, ureidopenicillins, cephalosporins, beta-lactam-betalactamase inhibitor combinations (such as piperacillin-tazobactam), folate antagonists, quinolones, and carbapenems. Many of these antibiotics also cover gram-positive bacteria. The antibiotics that specifically target gram-negative bacteria include aminoglycosides, monobactams (such as aztreonam), and ciprofloxacin.

Characteristics

File:Gram negative cell wall.svg
Gram-negative (LPS-diderm) cell wall structure
File:Gram-Cell-wall.svg
Gram-positive and gram-negative bacteria are differentiated chiefly by their cell wall structure

Conventional gram-negative (LPS-diderm) bacteria display the following characteristics:[citation needed]

However, the LPS-diderm group (corresponding to kingdom Pseudomonadati, formerly "Hydrobacteria") is not the only type of bacteria that stain negative.[4] Mycobacterium (or rather most of Mycobacteriales), which does not belong in the group, have independently evolved an outer cell membrane, with a cell wall made of mycolic acid.[5] This gives it very different structure and features.[6][7][8][9]

In many gram-negative bacteria, the IgaA membrane protein negatively regulates the Rcs phosphorelay system, a key envelope stress response pathway that helps maintain cell envelope integrity.

Classification

Along with cell shape, Gram staining is a rapid diagnostic tool and once was used to group species at the subdivision of Bacteria. Historically, the kingdom Monera was divided into four divisions based on Gram staining: Firmicutes (+), Gracillicutes (−), Mollicutes (0) and Mendocutes (var.).[10] Since 1987, the monophyly of the gram-negative bacteria has been disproven with molecular studies.[11]

Current knowledge divides the gram-negative bacteri into two large groups and some straddlers. The more "conventional" with an LPS outer membrane do share a common ancestor and are grouped in kingdom Pseudomonadati.[4] The less conventional ones are the order Mycobacteriales, that have a mycolic acid cell wall and an outer membrane.[5] The kingdom and the order are each monophyletic (or rather, not holyphyletic), but the "LPS-diderm" and "mycolic-diderm" groups are not, because some bacteria in the kingdom and the order do not stain gram negative. They will be discussed in the next section.

Taxonomy

Main article: Bacterial taxonomy
Further information: Bacteria § Classification and identification

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Bacteria are traditionally classified based on their Gram-staining response into the gram-positive and gram-negative bacteria. Having just one membrane, the gram-positive bacteria are also known as monoderm bacteria, while gram-negative bacteria, having two membranes, are also known as diderm bacteria. It was traditionally thought that the groups represent lineages, i.e., the extra membrane only evolved once, such that gram-negative bacteria are more closely related to one another than to any gram-positive bacteria. While this is often true, the classification system breaks down in some cases, with lineage groupings not matching the staining result.[12][13][6][7] Thus, Gram staining cannot be reliably used to assess familial relationships of bacteria. Nevertheless, staining often gives reliable information about the composition of the cell membrane, distinguishing between the presence or absence of an outer lipid membrane.[12][14]

Of these two structurally distinct groups of prokaryotic organisms, monoderm prokaryotes are thought to be ancestral. Based upon a number of different observations, including that the gram-positive bacteria are the most sensitive to antibiotics and that the gram-negative bacteria are, in general, resistant to antibiotics, it has been proposed that the outer cell membrane in gram-negative bacteria (diderms) evolved as a protective mechanism against antibiotic selection pressure.[12][13][14][8] Some bacteria such as Deinococcus, which stain gram-positive due to the presence of a thick peptidoglycan layer, but also possess an outer cell membrane are suggested as intermediates in the transition between monoderm (gram-positive) and diderm (gram-negative) bacteria.[12][8]

The conventional LPS-diderm group of gram-negative bacteria (e.g., Pseudomonadota, Aquificota, Chlamydiota, Bacteroidota, Chlorobiota, Cyanobacteria, Fibrobacterota, Verrucomicrobiota, Planctomycetota, Spirochaetota, Acidobacteriota) are uniquely identified by a few conserved signature indel (CSI) in the HSP60 (GroEL) protein. The presence of this CSI in all sequenced species of conventional lipopolysaccharide-containing gram-negative bacterial phyla provides evidence that these phyla of bacteria form a monophyletic clade and that no loss of the outer membrane from any species from this group has occurred.[8] They have accordingly been assigned a kingdom Pseudomonadati (formerly "Hydrobacteria").[4]

The difficulty lies in the other taxa that also have a diderm structure.

Example species

The proteobacteria are a major superphylum of gram-negative bacteria, including E. coli, Salmonella, Shigella, and other Enterobacteriaceae, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas, Bdellovibrio, acetic acid bacteria, Legionella etc. Other notable groups of gram-negative bacteria include the cyanobacteria, spirochaetes, and green sulfur bacteria.[16][17][18]

Medically relevant gram-negative diplococci include the four types that cause a sexually transmitted disease (Neisseria gonorrhoeae[19]), a meningitis (Neisseria meningitidis[20]), and respiratory symptoms (Moraxella catarrhalis,[21] A coccobacillus Haemophilus influenzae is another medically relevant coccal type.[22]

Medically relevant gram-negative bacilli include a multitude of species. Some of them cause primarily respiratory problems (Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa), primarily urinary problems (Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens), and primarily gastrointestinal problems (Helicobacter pylori, Salmonella enteritidis, Salmonella typhi).[23]

Gram-negative bacteria associated with hospital-acquired infections include Acinetobacter baumannii, which cause bacteremia, secondary meningitis, and ventilator-associated pneumonia in hospital intensive-care units.

Bacterial transformation

Transformation is one of three processes for horizontal gene transfer, in which exogenous genetic material passes from one bacterium to another, the other two being conjugation (transfer of genetic material between two bacterial cells in direct contact) and transduction (injection of foreign DNA by a bacteriophage virus into the host bacterium).[24][25] In transformation, the genetic material passes through the intervening medium, and uptake is completely dependent on the recipient bacterium.[24]

As of 2014 about 80 species of bacteria were known to be capable of transformation, about evenly divided between gram-positive and gram-negative bacteria; the number might be an overestimate since several of the reports are supported by single papers.[24] Transformation has been studied in medically important gram-negative bacteria species such as Helicobacter pylori, Legionella pneumophila, Neisseria meningitidis, Neisseria gonorrhoeae, Haemophilus influenzae and Vibrio cholerae.[26] It has also been studied in gram-negative species found in soil such as Pseudomonas stutzeri, Acinetobacter baylyi, and gram-negative plant pathogens such as Ralstonia solanacearum and Xylella fastidiosa.[26]

Role in disease

File:Diagnostic algorithm of possible bacterial infection.png
Example of a workup algorithm of possible bacterial infection in cases with no specifically requested targets (non-bacteria, mycobacteria etc.), with most common situations and agents seen in a New England setting. Clinically significant gram-negative bacteria are usually rods, as shown near bottom right. Although some gram-negative bacteria can be recognized by "bench tests", diagnosis in the modern microbiology lab usually involves MALDI-TOF and/or multitarget assay.

One of the several unique characteristics of gram-negative bacteria is the structure of the bacterial outer membrane. The outer leaflet of this membrane contains lipopolysaccharide (LPS), whose lipid A portion acts as an endotoxin.[1] If gram-negative bacteria enter the circulatory system, LPS can trigger an innate immune response, activating the immune system and producing cytokines (hormonal regulators). This leads to inflammation and can cause a toxic reaction, resulting in fever, an increased respiratory rate, and low blood pressure. That is why some infections with gram-negative bacteria can lead to life-threatening septic shock.[3]

The outer membrane protects the bacteria from several antibiotics, dyes, and detergents that would normally damage either the inner membrane or the cell wall (made of peptidoglycan). The outer membrane provides these bacteria with resistance to lysozyme and penicillin. The periplasmic space (space between the two cell membranes) also contains enzymes which break down or modify antibiotics. Drugs commonly used to treat Gram negative infections include amino, carboxy and ureido penicillins (ampicillin, amoxicillin, pipercillin, ticarcillin). These drugs may be combined with beta-lactamase inhibitors to combat the presence of enzymes that can digest these drugs (known as beta-lactamases) in the peri-plasmic space. Other classes of drugs that have Gram negative spectrum include cephalosporins, monobactams (aztreonam), aminoglycosides, quinolones, macrolides, chloramphenicol, folate antagonists, and carbapenems.[27]

Orthography: capitalization

The adjectives Gram-positive and Gram-negative derive from the surname of Hans Christian Gram, a Danish bacteriologist; as eponymous adjectives, their initial letter G can be either capital or lower-case, depending on which style guide is being adopted. For instance, the style guide of the American CDC recommends writing: Gram stain, this species is gram negative, and a gram-negative species.[28] [29]

See also

References

  • Public Domain This article incorporates public domain material from the NCBI document: "Science Primer".

Notes

  1. ↑ 1.0 1.1 Baron S, Salton MR, Kim KS (1996). "Structure". In Baron S (ed.). Medical Microbiology (4th ed.). University of Texas Medical Branch at Galveston. ISBN 978-0-9631172-1-2. PMID 21413343. Archived from the original on 2021-07-06. Retrieved 2021-08-18.
  2. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  3. ↑ 3.0 3.1 Pelletier, Lawrence L. (1996). "Microbiology of the Circulatory System". In Baron S (ed.). Medical Microbiology (4th ed.). University of Texas Medical Branch at Galveston. ISBN 978-0-9631172-1-2. PMID 21413321. Archived from the original on 2022-04-13. Retrieved 2021-05-12.
  4. ↑ 4.0 4.1 4.2 Göker, Markus; Oren, Aharon (22 January 2024). "Valid publication of names of two domains and seven kingdoms of prokaryotes". International Journal of Systematic and Evolutionary Microbiology. 74 (1). doi:10.1099/ijsem.0.006242. PMID 38252124 Check |pmid= value (help).
  5. ↑ 5.0 5.1 5.2 Gupta, Radhey S. (22 February 2019). "Commentary: Genome-Based Taxonomic Classification of the Phylum Actinobacteria". Frontiers in Microbiology. 10: 206. doi:10.3389/fmicb.2019.00206. PMC 6395429. PMID 30853945. Mycolic acids are important constituents of the cell envelopes of most members.
  6. ↑ 6.0 6.1 Desvaux M, Hébraud M, Talon R, Henderson IR (April 2009). "Secretion and subcellular localizations of bacterial proteins: a semantic awareness issue". Trends Microbiol. 17 (4): 139–45. doi:10.1016/j.tim.2009.01.004. PMID 19299134.
  7. ↑ 7.0 7.1 7.2 Sutcliffe IC (October 2010). "A phylum level perspective on bacterial cell envelope architecture". Trends Microbiol. 18 (10): 464–70. doi:10.1016/j.tim.2010.06.005. PMID 20637628.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Gupta RS (August 2011). "Origin of diderm (gram-negative) bacteria: antibiotic selection pressure rather than endosymbiosis likely led to the evolution of bacterial cells with two membranes". Antonie van Leeuwenhoek. 100 (2): 171–82. doi:10.1007/s10482-011-9616-8. PMC 3133647. PMID 21717204.
  9. ↑ 9.0 9.1 Marchandin H, Teyssier C, Campos J, Jean-Pierre H, Roger F, Gay B, Carlier JP, Jumas-Bilak E (June 2010). "Negativicoccus succinicivorans gen. nov., sp. nov., isolated from human clinical samples, emended description of the family Veillonellaceae and description of Negativicutes classis nov., Selenomonadales ord. nov. and Acidaminococcaceae fam. nov. in the bacterial phylum Firmicutes". Int. J. Syst. Evol. Microbiol. 60 (Pt 6): 1271–9. doi:10.1099/ijs.0.013102-0. PMID 19667386.
  10. ↑ Gibbons, N. E.; Murray, R. G. E. (1978). "Proposals Concerning the Higher Taxa of Bacteria". International Journal of Systematic Bacteriology. 28 (1): 1–6. doi:10.1099/00207713-28-1-1.
  11. ↑ Woese CR (June 1987). "Bacterial evolution". Microbiol. Rev. 51 (2): 221–71. doi:10.1128/MMBR.51.2.221-271.1987. PMC 373105. PMID 2439888.
  12. ↑ 12.0 12.1 12.2 12.3 Gupta, RS (December 1998). "Protein phylogenies and signature sequences: A reappraisal of evolutionary relationships among archaebacteria, eubacteria, and eukaryotes". Microbiol. Mol. Biol. Rev. 62 (4): 1435–91. doi:10.1128/MMBR.62.4.1435-1491.1998. PMC 98952. PMID 9841678.
  13. ↑ 13.0 13.1 Gupta RS (2000). "The natural evolutionary relationships among prokaryotes" (PDF). Crit. Rev. Microbiol. 26 (2): 111–31. CiteSeerX 10.1.1.496.1356. doi:10.1080/10408410091154219. PMID 10890353. S2CID 30541897. Archived (PDF) from the original on 2018-07-20. Retrieved 2017-10-24.
  14. ↑ 14.0 14.1 Gupta RS (August 1998). "What are archaebacteria: life's third domain or monoderm prokaryotes related to gram-positive bacteria? A new proposal for the classification of prokaryotic organisms". Mol. Microbiol. 29 (3): 695–707. doi:10.1046/j.1365-2958.1998.00978.x. PMID 9723910.
  15. ↑ Choi, JK; Poudel, S; Yee, N; Goff, JL (3 October 2024). "Deeply branching Bacillota species exhibit atypical Gram-negative staining". Microbiology Spectrum. 12 (10): e0073224. doi:10.1128/spectrum.00732-24. PMC 11448272 Check |pmc= value (help). PMID 39162559 Check |pmid= value (help).
  16. ↑ Castenholz, Richard W. (2015), "General Characteristics of the Cyanobacteria", Bergey's Manual of Systematics of Archaea and Bacteria, John Wiley & Sons, Ltd, pp. 1–23, doi:10.1002/9781118960608.cbm00019, ISBN 978-1-118-96060-8, retrieved 2025-01-25
  17. ↑ Cole, John R. (1990-01-01), Carter, G. R.; Cole, John R. (eds.), "5 - Spirochetes", Diagnostic Procedure in Veterinary Bacteriology and Mycology (Fifth Edition), San Diego: Academic Press, pp. 41–60, doi:10.1016/b978-0-12-161775-2.50009-8, ISBN 978-0-12-161775-2, retrieved 2025-01-25
  18. ↑ Schmidt, Thomas M. (2019). Encyclopedia of Microbiology (4th ed.). San Diego: Elsevier Science & Technology. pp. 527–537. ISBN 978-0-12-811737-8.
  19. ↑ Yeshanew, Addisu Gize; Geremew, Rozina Ambachew (2018-07-17). "MNeisseria Gonorrhoae and their antimicrobial susceptibility patterns among symptomatic patients from Gondar town, north West Ethiopia". Antimicrobial Resistance and Infection Control. 7 (85): 85. doi:10.1186/s13756-018-0376-3. PMC 6050735. PMID 30026943.
  20. ↑ "Vaccine Preventable Diseases Surveillance Manual". CDC. April 3, 2018. Retrieved January 26, 2024.
  21. ↑ Verduin, Cees M.; Hol, Cees; Fleer, Andre; van Dijk, Hans; van Belkum, Alex (January 2002). "Moraxella catarrhalis: from Emerging to Established Pathogen". Clinical Microbiology Reviews. 15 (1): 125–144. doi:10.1128/CMR.15.1.125-144.2002. PMC 118065. PMID 11781271.
  22. ↑ "For Clinicians: Haemophilus influenzae". CDC. February 13, 2018. Retrieved January 26, 2024.
  23. ↑ Ryan, Kenneth J. (2022). "18-25". Sherris Medical Microbiology (8th ed.). McGraw-Hill Education. ISBN 978-1260464283. Gram-negative bacilli are a diverse group of bacteria with distinct clinical niches, ranging from the respiratory tract (e.g., Pseudomonas, Legionella) to the urinary tract (e.g., E. coli, Proteus) and the gastrointestinal system (e.g., Salmonella, Helicobacter).
  24. ↑ 24.0 24.1 24.2 Johnston C, Martin B, Fichant G, Polard P, Claverys JP (2014). "Bacterial transformation: distribution, shared mechanisms and divergent control". Nat. Rev. Microbiol. 12 (3): 181–96. doi:10.1038/nrmicro3199. PMID 24509783. S2CID 23559881.
  25. ↑ Korotetskiy I, Shilov S, Kuznetsova T, Kerimzhanova B, Korotetskaya N, Ivanova L, Zubenko N, Parenova R, Reva O (2023). "Analysis of Whole-Genome Sequences of Pathogenic Gram-Positive and Gram-Negative Isolates from the Same Hospital Environment to Investigate Common Evolutionary Trends Associated with Horizontal Gene Exchange, Mutations and DNA Methylation Patterning". Microorganisms. 11 (2): 323. doi:10.3390/microorganisms11020323. PMC 9961978 Check |pmc= value (help). PMID 36838287 Check |pmid= value (help).
  26. ↑ 26.0 26.1 Seitz P, Blokesch M (2013). "Cues and regulatory pathways involved in natural competence and transformation in pathogenic and environmental Gram-negative bacteria". FEMS Microbiol. Rev. 37 (3): 336–63. doi:10.1111/j.1574-6976.2012.00353.x. PMID 22928673.
  27. ↑ Glück, Thomas (12 December 2003). "Gram-Negative Bacteria and Broad-Spectrum Antibiotics: Good News Except for Fluoroquinolones". www.jwatch.org. NEJM Journal Watch. Archived from the original on 10 March 2018. Retrieved 10 March 2018.
  28. ↑ "Emerging Infectious Diseases Journal Style Guide". CDC.gov. Centers for Disease Control and Prevention.
  29. ↑ "Preferred Usage - Emerging Infectious Disease journal - CDC". CDC.gov. Centers for Disease Control and Prevention. Archived from the original on 2018-01-29. Retrieved 2018-03-04.

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