Mycobacterium

File:Model of the Mycobacterial Cell Envelope.png

Mycobacteria are aerobic with 0.2-0.6 μm wide and 1.0-10 μm long rod shapes. They are generally non-motile, except for the species Mycobacterium marinum, which has been shown to be motile within macrophages.{{cite journal | vauthors = Stamm LM, Morisaki JH, Gao LY, Jeng RL, McDonald KL, Roth R, Takeshita S, Heuser J, Welch MD, Brown EJ | display-authors = 6 | title = Mycobacterium marinum escapes from phagosomes and is propelled by actin-based motility | journal = The Journal of Experimental Medicine | volume = 198 | issue = 9 | pages = 1361–1368 | date = November 2003 | pmid = 14597736 | pmc = 2194249 | doi = 10.1084/jem.20031072 }} Mycobacteria possess capsules and most do not form endospores. M. marinum and perhaps M. bovis have been shown to sporulate;{{cite journal | vauthors = Ghosh J, Larsson P, Singh B, Pettersson BM, Islam NM, Sarkar SN, Dasgupta S, Kirsebom LA | display-authors = 6 | title = Sporulation in mycobacteria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 26 | pages = 10781–10786 | date = June 2009 | pmid = 19541637 | pmc = 2705590 | doi = 10.1073/pnas.0904104106 | doi-access = free | bibcode = 2009PNAS..10610781G }} however, this has been contested by further research.{{cite journal | vauthors = Traag BA, Driks A, Stragier P, Bitter W, Broussard G, Hatfull G, Chu F, Adams KN, Ramakrishnan L, Losick R | display-authors = 6 | title = Do mycobacteria produce endospores? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 2 | pages = 878–881 | date = January 2010 | pmid = 20080769 | pmc = 2818926 | doi = 10.1073/pnas.0911299107 | doi-access = free | bibcode = 2010PNAS..107..878T }} The distinguishing characteristic of all Mycobacterium species is a thick, hydrophobic, and mycolic acid-rich cell wall made of peptidoglycan and arabinogalactan, with these unique components offering targets for new tuberculosis drugs.{{cite book | vauthors = Bhamidi S|year=2009|chapter=Mycobacterial Cell Wall Arabinogalactan|title=Bacterial Polysaccharides: Current Innovations and Future Trends|publisher=Caister Academic Press|isbn= 978-1-904455-45-5}}

Many Mycobacterium species readily grow with minimal nutrients, using ammonia and/or amino acids as nitrogen sources and glycerol as a carbon source in the presence of mineral salts. Temperatures for optimal growth vary between species and media conditions, ranging from 25 to 45 °C.

Most Mycobacterium species, including most clinically relevant species, can be cultured in blood agar.{{cite journal | vauthors = Lagier JC, Edouard S, Pagnier I, Mediannikov O, Drancourt M, Raoult D | title = Current and past strategies for bacterial culture in clinical microbiology | journal = Clinical Microbiology Reviews | volume = 28 | issue = 1 | pages = 208–236 | date = January 2015 | pmid = 25567228 | pmc = 4284306 | doi = 10.1128/CMR.00110-14 }} However, some species grow very slowly due to extremely long reproductive cycles, such as M. leprae requiring 12 days per division cycle compared to 20 minutes for some E. coli strains.{{cite journal | vauthors = Shepard CC, Mcrae DH | title = Mycobacterium leprae in Mice: Minimal Infectious Dose, Relationship Between Staining Quality and Infectivity, and Effect of Cortisone | journal = Journal of Bacteriology | volume = 89 | issue = 2 | pages = 365–372 | date = February 1965 | pmid = 14255702 | pmc = 305516 | doi = 10.1128/jb.89.2.365-372.1965 }}

Whereas Mycobacterium tuberculosis and M. leprae are pathogenic, most mycobacteria do not cause disease unless they enter skin lesions of those with pulmonary and/or immune dysfunction, despite being widespread across aquatic and terrestrial environments. Through biofilm formation, cell wall resistance to chlorine, and association with amoebas, mycobacteria can survive a variety of environmental stressors. The agar media used for most water testing does not support the growth of mycobacteria, allowing it to go undetected in municipal and hospital systems.{{cite journal | vauthors = Vaerewijck MJ, Huys G, Palomino JC, Swings J, Portaels F | title = Mycobacteria in drinking water distribution systems: ecology and significance for human health | journal = FEMS Microbiology Reviews | volume = 29 | issue = 5 | pages = 911–934 | date = November 2005 | pmid = 16219512 | doi = 10.1016/j.femsre.2005.02.001 | doi-access = free }}

Hundreds of Mycobacterium genomes have been completely sequenced.{{Cite web |title=JGI GOLD {{!}} Projects |url=https://gold.jgi.doe.gov/projects?Project.Is+Public=Yes&Organism.Organism+Name=Mycobacterium&Organism.Organism+Name=Mycobacterium&Project.Project+Status=Complete+and+Published&Project.Is+Public=Yes&Project.Project+Status=Complete+and+Published |access-date=2023-05-13 |website=gold.jgi.doe.gov}}

The genome sizes of mycobacteria range from relatively small ones (e.g. in M. leprae) to quite large ones, such as that as M. vulneris, encoding 6,653 proteins, larger than the ~6000 proteins of eukaryotic yeast.{{cite journal |vauthors=Croce O, Robert C, Raoult D, Drancourt M |date=May 2014 |title=Draft Genome Sequence of Mycobacterium vulneris DSM 45247T |journal=Genome Announcements |volume=2 |issue=3 |doi=10.1128/genomeA.00370-14 |pmc=4014686 |pmid=24812218}}

Mycobacterium tuberculosis can remain latent in human hosts for decades after an initial infection, allowing it to continue infecting others. It has been estimated that a third of the world population has latent tuberculosis (TB).{{cite journal | vauthors = Getahun H, Matteelli A, Chaisson RE, Raviglione M | title = Latent Mycobacterium tuberculosis infection | journal = The New England Journal of Medicine | volume = 372 | issue = 22 | pages = 2127–2135 | date = May 2015 | pmid = 26017823 | doi = 10.1056/NEJMra1405427 }} M. tuberculosis has many virulence factors, which can be divided across lipid and fatty acid metabolism, cell envelope proteins, macrophage inhibitors, kinase proteins, proteases, metal-transporter proteins, and gene expression regulators.{{cite journal | vauthors = Forrellad MA, Klepp LI, Gioffré A, Sabio y García J, Morbidoni HR, de la Paz Santangelo M, Cataldi AA, Bigi F | display-authors = 6 | title = Virulence factors of the Mycobacterium tuberculosis complex | journal = Virulence | volume = 4 | issue = 1 | pages = 3–66 | date = January 2013 | pmid = 23076359 | pmc = 3544749 | doi = 10.4161/viru.22329 }} Several lineages such as M. t. var. bovis (bovine TB) were considered separate species in the M, tuberculosis complex until they were finally merged into the main species in 2018.{{cite journal |last1=Riojas |first1=Marco A. |last2=McGough |first2=Katya J. |last3=Rider-Riojas |first3=Cristin J. |last4=Rastogi |first4=Nalin |last5=Hazbón |first5=Manzour Hernando |title=Phylogenomic analysis of the species of the Mycobacterium tuberculosis complex demonstrates that Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae, Mycobacterium microti and Mycobacterium pinnipedii are later heterotypic synonyms of Mycobacterium tuberculosis |journal=International Journal of Systematic and Evolutionary Microbiology |date=1 January 2018 |volume=68 |issue=1 |pages=324–332 |doi=10.1099/ijsem.0.002507|pmid=29205127 |doi-access=free }}

The development of leprosy is caused by infection with either Mycobacterium leprae or Mycobacterium lepromatosis, two closely related bacteria. Roughly 200,000 new cases of infection are reported each year, and 80% of new cases are reported in Brazil, India, and Indonesia.{{cite journal | vauthors = Sugawara-Mikami M, Tanigawa K, Kawashima A, Kiriya M, Nakamura Y, Fujiwara Y, Suzuki K | title = Pathogenicity and virulence of Mycobacterium leprae | journal = Virulence | volume = 13 | issue = 1 | pages = 1985–2011 | date = December 2022 | pmid = 36326715 | pmc = 9635560 | doi = 10.1080/21505594.2022.2141987 }} M. leprae infection localizes within the skin macrophages and Schwann cells found in peripheral nerve tissue.

File:Three Pathogenic Mycobacteria.png proteins found in each species (based on OMA identifiers). Unique proteins for each species are localized in the outer section for each species.]]

Nontuberculosis Mycobacteria (NTM), which exclude M. tuberculosis, M. leprae, and M. lepromatosis, can infect mammalian hosts. These bacteria are referred to as "atypical mycobacteria." Although person-to-person transmission is rare, transmission of M. abscessus has been observed between patients with cystic fibrosis.{{Cite web |date=2019-08-12 |title=Nontuberculous Mycobacteria (NTM) Infections {{!}} HAI {{!}} CDC |url=https://www.cdc.gov/hai/organisms/nontuberculous-mycobacteria.html |access-date=2023-04-28 |website=www.cdc.gov |language=en-us}} The four primary diseases observed in humans are chronic pulmonary disease, disseminated disease in immunocompromised patients, skin and soft tissue infections, and superficial lymphadenitis. 80-90% of recorded NTM infections manifest as pulmonary diseases.{{cite journal | vauthors = To K, Cao R, Yegiazaryan A, Owens J, Venketaraman V | title = General Overview of Nontuberculous Mycobacteria Opportunistic Pathogens: Mycobacterium avium and Mycobacterium abscessus | journal = Journal of Clinical Medicine | volume = 9 | issue = 8 | pages = 2541 | date = August 2020 | pmid = 32781595 | pmc = 7463534 | doi = 10.3390/jcm9082541 | doi-access = free }}

M. abscessus is the most virulent rapidly-growing mycobacterium (RGM), as well as the leading cause of RGM based pulmonary infections. Although it has been traditionally viewed as an opportunistic pathogen like other NTMs, analysis of various virulence factors (VFs) have shifted this view to that of a true pathogen. This is due to the presence of known mycobacterial VFs and other non-mycobacterial VFs found in other prokaryotic pathogens.

Mycobacteria have cell walls with peptidoglycan, arabinogalactan, and mycolic acid; a waxy outer mycomembrane of mycolic acid; and an outermost capsule of glucans and secreted proteins for virulence. It constantly remodels these layers to survive in stressful environments and avoid host immune defenses. This cell wall structure results in colony surfaces resembling fungi, leading to the genus' use of the Greek prefix myco-.{{cite web |title=Mycobacteria: Health Advisory EPA-822-B-01-007 |url=https://www.epa.gov/sites/default/files/2015-10/documents/mycobacteria-report.pdf |website=epa.gov |publisher=US Environmental Protection Agency (EPA) |access-date=10 March 2023 |page=2 |date=August 1999}} This unique structure makes penicillins ineffective, instead requiring a multi-drug antibiotic treatment of isoniazid to inhibit mycolic acid synthesis, rifampicin to interfere with transcription, ethambutol to hinder arabinogalactan synthesis, and pyrazinamide to impede coenzyme A synthesis.{{cite journal | vauthors = Dulberger CL, Rubin EJ, Boutte CC | title = The mycobacterial cell envelope - a moving target | journal = Nature Reviews. Microbiology | volume = 18 | issue = 1 | pages = 47–59 | date = January 2020 | pmid = 31728063 | doi = 10.1038/s41579-019-0273-7 | s2cid = 208020338 }}

{{cladogram|title=Cladogram of Key Species

|caption=

|clades={{clade| style=font-size:75%;line-height:75%;

|1={{clade

|label1=Mycobacterium

|1={{clade

|1={{clade

|1=M. chelonae

|2={{clade

|1=M. fortuitum

|2={{clade

|1=M. flavescens

|2=M. smegmatis

}}

}}

}}

|2={{clade

|1={{clade

|1={{clade

|1={{clade

|1={{clade

|1={{clade

|1={{clade

|1={{clade

|1=M. avium

|2=M. intracellulare

}}

|2={{clade

|1=M. kansasii

|2=M. scrofulaceum

}}

}}

|2={{clade

|1=M. malmoense

|2=M. szulgai

}}

}}

|2={{clade

|1=M. marinum

|2=M. tuberculosis

}}

}}

|2=M. gordonae

}}

|2=M. simiae

}}

|2=M. xenopi

}}

|2={{clade

|1=M. nonchromogenicum

|2=M. terrae

}}

}}

}}

|label2=outgroup

|2=Nocardia asteroides

}}

}}}}

Mycobacteria have historically been categorized through phenotypic testing, such as the Runyon classification of analyzing growth rate and production of yellow/orange carotenoid pigments. Group I contains photochromogens (pigment production induced by light), Group II comprises scotochromogens (constitutive pigment production), and the non-chromogens of Groups III and IV have a pale yellow/tan pigment, regardless of light exposure. Group IV species are "rapidly-growing" mycobacteria compared to the "slowly-growing" Group III species because samples grow into visible colonies in less than seven days.

Because the International Code of Nomenclature of Prokaryotes (ICNP) currently recognizes 195 Mycobacterium species, classification and identification systems now rely on DNA sequencing and computational phylogenetics. The major disease-causing groups are the M. tuberculosis complex (tuberculosis), M. avium complex (mycobacterium avium-intracellulare infection), M. leprae and M. lepromatosis (leprosy), and M. abscessus (chronic lung infection).

Microbiologist Enrico Tortoli has constructed a phylogenetic tree of the genus' key species based on the earlier genetic sequencing of Rogall, et al. (1990), alongside new phylogentic trees based on Tortoli's 2017 sequencing of 148 Mycobacterium species:{{cite book | vauthors = Tortoli E | chapter = Chapter 1 - The Taxonomy of the Genus Mycobacterium |date=2019-01-10 | doi = 10.1016/B978-0-12-814692-7.00001-2 |title = Nontuberculous Mycobacteria (NTM) |pages=1–10 | veditors = Velayati AA, Farnia P |publisher=Academic Press |language=en |isbn=978-0-12-814692-7 | s2cid = 92810288 }}

File:Phylogentic Tree of Slowly-Growing Mycobacterium Tortoli 2017.png|Phylogenetic tree of slowly-growing members of the Mycobacterium genus

File:Phylogentic Tree of Rapidly-Growing Mycobacterium Tortoli 2017.png|Phylogenetic tree of rapidly-growing members of the Mycobacterium genus, alongside the M. terrae complex.{{cite journal | vauthors = Tortoli E, Fedrizzi T, Meehan CJ, Trovato A, Grottola A, Giacobazzi E, Serpini GF, Tagliazucchi S, Fabio A, Bettua C, Bertorelli R, Frascaro F, De Sanctis V, Pecorari M, Jousson O, Segata N, Cirillo DM | display-authors = 6 | title = The new phylogeny of the genus Mycobacterium: The old and the news | journal = Infection, Genetics and Evolution | volume = 56 | pages = 19–25 | date = December 2017 | pmid = 29030295 | doi = 10.1016/j.meegid.2017.10.013 | bibcode = 2017InfGE..56...19T }}

Gupta et al. have proposed dividing Mycobacterium into five genera, based on an analysis of 150 species in this genus. Due to controversy over complicating clinical diagnoses and treatment, all of the renamed species have retained their original identity in the Mycobacterium genus as a valid taxonomic synonym:{{cite journal | vauthors = Gupta RS, Lo B, Son J | title = Phylogenomics and Comparative Genomic Studies Robustly Support Division of the Genus Mycobacterium into an Emended Genus Mycobacterium and Four Novel Genera | journal = Frontiers in Microbiology | volume = 9 | pages = 67 | year = 2018 | pmid = 29497402 | pmc = 5819568 | doi = 10.3389/fmicb.2018.00067 | doi-access = free }}{{cite journal | vauthors = Tortoli E, Brown-Elliott BA, Chalmers JD, Cirillo DM, Daley CL, Emler S, Floto RA, Garcia MJ, Hoefsloot W, Koh WJ, Lange C, Loebinger M, Maurer FP, Morimoto K, Niemann S, Richter E, Turenne CY, Vasireddy R, Vasireddy S, Wagner D, Wallace RJ, Wengenack N, van Ingen J | display-authors = 6 | title = Same meat, different gravy: ignore the new names of mycobacteria | journal = The European Respiratory Journal | volume = 54 | issue = 1 | pages = 1900795 | date = July 2019 | pmid = 31296783 | doi = 10.1183/13993003.00795-2019 | doi-access = free }}

• Mycobacterium based on the Slowly-Growing Tuberculosis-Simiae clade
• Mycobacteroides based on the Rapidly-Growing Abscessus-Chelonae clade
• Mycolicibacillus based on the Slowly-Growing Triviale clade
• Mycolicibacter based on the Slowly-Growing Terrae clade
• Mycolicibacterium based on the Rapidly-Growing Fortuitum-Vaccae clade

{{further|Bacterial taxonomy#Pathology vs. phylogeny}}

The two most common methods for visualizing these acid-fast bacilli as bright red against a blue background are the Ziehl-Neelsen stain and modified Kinyoun stain. Fite's stain is used to color M. leprae cells as pink against a blue background. Rapid Modified Auramine O Fluorescent staining has specific binding to slowly-growing mycobacteria for yellow staining against a dark background. Newer methods include Gomori-Methenamine Silver staining and Perioidic Acid Schiff staining to color Mycobacterium avium complex (MAC) cells black and pink, respectively.

While some mycobacteria can take up to eight weeks to grow visible colonies from a cultured sample, most clinically relevant species will grow within the first four weeks, allowing physicians to consider alternative causes if negative readings continue past the first month.{{cite journal | vauthors = Ogwang S, Mubiri P, Bark CM, Joloba ML, Boom WH, Johnson JL | title = Incubation time of Mycobacterium tuberculosis complex sputum cultures in BACTEC MGIT 960: 4weeks of negative culture is enough for physicians to consider alternative diagnoses | journal = Diagnostic Microbiology and Infectious Disease | volume = 83 | issue = 2 | pages = 162–164 | date = October 2015 | pmid = 26239846 | pmc = 4573350 | doi = 10.1016/j.diagmicrobio.2015.07.002 }} Growth media include Löwenstein–Jensen medium and mycobacteria growth indicator tube (MGIT).

File:Mycobacterium tuberculosis Ziehl-Neelsen stain 02.jpg|Mycobacterium tuberculosis on Ziehl-Neelsen stain

File:Slant tubes of Löwenstein-Jensen medium with control, M tuberculosis, M avium and M gordonae.jpg|Slant tubes of Löwenstein-Jensen medium.From left to right in image of slant tubes of Löwenstein-Jensen medium:
- Negative control
- M. tuberculosis: Dry-appearing colonies
- Mycobacterium avium complex: Wet-appearing colonies
- M. gordonae: Yellowish colonies

File:Mycobacteria Growth Indicator Tube (MGIT) samples in ultraviolet light.jpg|MGIT samples emitting fluorescence in ultraviolet light

Mycobacteria can be infected by mycobacteriophages, a class of viruses with high specificity for their targets. By hijacking the cellular machinery of mycobacteria to produce additional phages, such viruses can be used in phage therapy for eukaryotic hosts, as they would die alongside the mycobacteria. Since only some mycobacteriophages are capable of penetrating the M. tuberculosis membrane, the viral DNA may be delivered through artificial liposomes because bacteria uptake, transcribe, and translate foreign DNA into proteins.{{cite journal | vauthors = Azimi T, Mosadegh M, Nasiri MJ, Sabour S, Karimaei S, Nasser A | title = Phage therapy as a renewed therapeutic approach to mycobacterial infections: a comprehensive review | language = English | journal = Infection and Drug Resistance | volume = 12 | pages = 2943–2959 | date = 2019-09-17 | pmid = 31571947 | pmc = 6756577 | doi = 10.2147/IDR.S218638 | doi-access = free }}

Mycosides are glycolipids isolated from Mycobacterium species with Mycoside A found in photochromogenic strains, Mycoside B in bovine strains, and Mycoside C in avian strains.{{cite journal | vauthors = Smith DW, Randall HM, Maclennan AP, Lederer E | title = Mycosides: a new class of type-specific glycolipids of Mycobacteria | journal = Nature | volume = 186 | issue = 4728 | pages = 887–888 | date = June 1960 | pmid = 13831939 | doi = 10.1038/186887a0 | s2cid = 4149360 | bibcode = 1960Natur.186..887S }} Different forms of Mycoside C have varying success as a receptor to inactivate mycobacteriophages.{{cite journal | vauthors = Goren MB, McClatchy JK, Martens B, Brokl O | title = Mycosides C: behavior as receptor site substance for mycobacteriophage D4 | journal = Journal of Virology | volume = 9 | issue = 6 | pages = 999–1003 | date = June 1972 | pmid = 4113889 | pmc = 356406 | doi = 10.1128/jvi.9.6.999-1003.1972 }} Replacement of the gene encoding mycocerosic acid synthase in M. bovis prevents formation of mycosides.{{cite journal | vauthors = Azad AK, Sirakova TD, Rogers LM, Kolattukudy PE | title = Targeted replacement of the mycocerosic acid synthase gene in Mycobacterium bovis BCG produces a mutant that lacks mycosides | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 10 | pages = 4787–4792 | date = May 1996 | pmid = 8643481 | pmc = 39357 | doi = 10.1073/pnas.93.10.4787 | doi-access = free | bibcode = 1996PNAS...93.4787A }}

{{Reflist|2}}

• [https://www.bv-brc.org/view/Taxonomy/1763 Bacterial and Viral Bioinformatics Resource Center]: Genomes, proteins, epitopes, and pathways of mycobacteria
• [https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria Merck Manual - Mycobacteria]
• [https://mycobrowser.epfl.ch/ Mycobrowser]: Genomic and proteomic database for pathogenic mycobacteria
• [https://www.cdc.gov/hai/organisms/nontuberculous-mycobacteria.html CDC - Nontuberculous Mycobacteria (NTM) Infections]
• [http://app.chuv.ch/prasite/index.html PRASITE: Identification of Mycobacteria]
• [https://web.archive.org/web/20170302163233/http://www.webtb.org/ TB Structural Genomics Consortium]

{{Mycobacteria}}

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Category:Acid-fast bacilli

Category:Tuberculosis

Category:Bacterial diseases

Category:Bacteria genera

Category:Pathogenic bacteria

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