Gram-negative bacteria: Difference between revisions - Wikipedia

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[[File:Pseudomonas aeruginosa Gram.jpg|thumb|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|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 their [[~~Cell envelope|~~cell ~~envelopes~~envelope]], which 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>{{cnCite journal |last1=Silhavy |first1=T. J. |last2=Kahne |first2=D. |last3=Walker |first3=S. |date=~~November~~2010-05-01 ~~2023~~|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]].

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>

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]]s, and [[carbapenem]]s. Many of these antibiotics also cover ~~[[Gram-positive bacteria|~~gram-positive]] bacteria. The antibiotics that specifically target gram-negative organisms include [[aminoglycoside]]s, [[monobactam]]s (such as [[aztreonam]]), and [[ciprofloxacin]].

== Characteristics ==

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[[File:Gram-Cell-wall.svg|thumb|right|[[Gram-positive]] and -negative [[bacteria]] are differentiated chiefly by their [[cell wall]] structure]]

Conventional gram-negative (LPS-diderm) bacteria display {{nowrap|~~these~~the following characteristics}}:{{cn|date=July 2022}}

* An inner [[cell membrane]] is present ([[cytoplasm]]ic)

* A thin [[peptidoglycan]] layer is present (this is much thicker in [[gram-positive bacteria]])

* Has [[Bacterial outer membrane|outer membrane]] containing [[lipopolysaccharide]]s (LPS, which consists of [[lipid A]], core [[polysaccharide]], and [[O antigen]]) in its outer leaflet and [[phospholipid]]s in the inner leaflet

* [[Porin (protein)|Porins]] exist in the outer membrane, which act like pores for particular molecules

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== Classification ==

Along with cell shape, [[Gram stain]]ing is a rapid diagnostic tool and once was used to group species at the subdivision of Bacteria.

[[Bacterial taxonomy#~~history~~History|Historically]], the kingdom [[Monera]] was divided into four [[Taxonomic rank|divisions]] based on Gram staining: [[Bacillota|Firmacutes]]  (+), [[Gracilicutes|Gracillicutes]] (−), [[Mollicutes]] (0) and [[Methanogen|Mendocutes]] (var.).<ref>{{cite journal |last1=Gibbons |first1=N. E. |last2=Murray |first2=R. G. E. |title=Proposals Concerning the Higher Taxa of Bacteria |journal=International Journal of Systematic Bacteriology |year=1978 |volume=28 |issue=1 |pages=1–6 |doi=10.1099/00207713-28-1-1 |doi-access=free }}</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> However some authors, such as [[Cavalier-Smith]] still treat them as a [[Monophyly|monophyletic]] [[taxon]] (though not a [[clade]]; his definition of [[monophyly]] requires a single common ancestor but does not require [[Monophyly|holophyly]], the property that all descendants be encompassed by the [[taxon]]) and refer to the group as a [[Kingdom (biology)|subkingdom]] "Negibacteria".<ref name="pmid16834776">{{cite journal |last= Cavalier-Smith |first=T. | title = Rooting the tree of life by transition analyses | journal = Biol. Direct | volume = 1 | pages = 19 | year = 2006 | pmid = 16834776 | pmc = 1586193 | doi = 10.1186/1745-6150-1-19 |doi-access=free }}</ref>

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{{Split section|Gram stain |discuss=Gram stain#Move Taxonomy sections here |date=November 2023}}

Bacteria are traditionally classified based on their [[Gram stain|Gram-stain]]ing response into the [[~~Gram-positive bacteria|~~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"/> The diderm bacteria can also be further differentiated between simple diderms lacking lipopolysaccharide (LPS); the archetypical diderm bacteria, in which the outer cell membrane contains lipopolysaccharide; and the diderm bacteria, in which the outer cell membrane is made up of [[mycolic acid]] (e. g. ''[[Mycobacterium]]'').<ref name="Desvaux et al., 2009"/><ref name="Sutcliffe, 2010"/><ref name="Guptac"/><ref name="pmid19667386">{{cite journal|vauthors=Marchandin H, Teyssier C, Campos J, Jean-Pierre H, Roger F, Gay B, Carlier JP, Jumas-Bilak E |title=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 |journal=Int. J. Syst. Evol. Microbiol. |volume=60 |issue=Pt 6 |pages=1271–9 |date=June 2010 |pmid=19667386 |doi=10.1099/ijs.0.013102-0|doi-access=free }}</ref>

The conventional LPS-''diderm'' group of gram-negative bacteria (e.g., [[Pseudomonadota]], [[Aquificota]], [[Chlamydiota]], [[Bacteroidota]], [[Chlorobiota]], "[[Cyanobacteria]]", [[Fibrobacterota]], [[Verrucomicrobiota]], [[Planctomycetota]], [[Spirochaetota]], [[Acidobacteriota]]; "[[Hydrobacteria]]") are uniquely identified by a few [[conserved signature indel]] (CSI) in the [[HSP60]] ([[GroEL]]) protein. In addition, a number of bacterial [[Taxon|taxa]] (including [[Negativicutes]], [[Fusobacteriota]], [[Synergistota]], and [[Elusimicrobiota]]) that are either part of the [[phylum]] [[Bacillota]] (a monoderm group) or branches in its proximity are also found to possess a diderm cell structure.<ref name="Sutcliffe, 2010"/><ref name="Guptac"/><ref name="pmid19667386"/> They lack the [[GroEL]] signature.<ref name="Guptac"/> 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"/>

=== 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, [[green sulfur bacteria|green sulfur]], and [[green non-sulfur bacteria]]<ref>{{Citation |last=Guentzel |first=M. Neal |title=Escherichia, Klebsiella, Enterobacter, Serratia, Citrobacter, and Proteus |date=1996 |work=Medical Microbiology |editor-last=Baron |editor-first=Samuel |url=http://www.ncbi.nlm.nih.gov/books/NBK8035/ |access-date=2024-03-28 |edition=4th |place=Galveston (TX) |publisher=University of Texas Medical Branch at Galveston |isbn=978-0-9631172-1-2 |pmid=21413290}}</ref>.{{cn|date=November 2023}}

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 [[Coccus|cocci]] include the four types that cause a [[sexually transmitted disease]] (''[[Neisseria gonorrhoeae]]''), a [[meningitis]] (''[[Neisseria meningitidis]]''), and respiratory symptoms (''[[Moraxella catarrhalis]]'', ''[[Haemophilus influenzae]]'').{{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]]'').{{cn|date=November 2023}}

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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"/>

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~~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]]), aminoglycosides, [[quinolone]]s, [[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>

== Orthographic note ==