Mycobacterium is a genus of over 190 species of Gram-positive bacteria in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis (M. tuberculosis) and leprosy (M. leprae) in humans. The Greek prefix myco- means 'fungus', alluding to this genus's mold-like colony surfaces. Since this genus has cell walls with a waxy lipid-rich outer layer containing high concentrations of mycolic acid, acid-fast staining is used to emphasize their resistance to acids, compared to other cell types.
Mycobacterial species are generally aerobic, non-motile, and capable of growing with minimal nutrition. The genus is divided based on each species's pigment production and growth rate. While most Mycobacterium species are non-pathogenic, the genus's characteristic complex cell wall contributes to evasion from host defenses. Mycobacteria possess capsules and most do not form endospores. M. marinum and perhaps M. bovis have been shown to sporulate; however, this has been contested by further research. 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.
Physiology
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. 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.
Ecology
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.
Genomics
Hundreds of Mycobacterium genomes have been completely sequenced.
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.
{| class="wikitable"
|+Protein-Coding Genomic Information
!Organism
!Number of Protein Coding Genes
|-
|M. intracellulare
|5,289
|-
|M. colombiense
|5,084
|-
|M. leprae
|1,603
|-
|M. tuberculosis
|3,995
|-
|M. chelonae
|4,948
|}
Pathogenicity
Mycobacterium tuberculosis complex
Mycobacterium tuberculosis can remain latent in human hosts for decades after an initial infection, and reactivate under conducive conditions (e.g. immune suppression, advanced age, malnutrition). It has been estimated that a third of the world population has latent tuberculosis (TB). 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. 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.
Leprosy
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. M. leprae infection localizes within the skin macrophages and Schwann cells found in peripheral nerve tissue.
Nontuberculosis Mycobacteria
thumb|[[Sequence homology|Orthologous 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. 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.
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. 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.
{| class="wikitable"
|+Mycobacterial Infection Information
!Organism
!Common Symptoms of Infection
!Known Treatments
!Reported Cases (Region, Year)
|-
|M. tuberculosis
|Fatigue, weight loss, fever, hemoptysis, chest pain.
|isoniazid INH, rifampin, pyrazinamide, ethambutol.
|1.6 Million (Global, 2021)
|-
|M. leprae
M. lepromatosis
|Skin discoloration, nodule development, dry skin, loss of eyebrows and/or eyelashes, numbness, nosebleeds, paralysis, blindness, nerve pain.
|dapson, rifampicin, clofazimine.
|-
|M. avium complex
|Tender skin, development of boils or pus-filled vesicles, fevers, chills, muscle aches.
|clarithromycin, azithromycin, amikacin, cefoxitin, imipenem.
|3000 (US, Annual estimated)
|-
|M. abscessus complex
|Coughing, hemoptysis, fever, cavitary lesions.
|clarithromycin, amikacin, cefoxitin, imipenem.
<gallery mode=packed heights=360>
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
</gallery>
Proposed division of the genus
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:
- 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
Diagnosis
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. Growth media include Löwenstein–Jensen medium and mycobacteria growth indicator tube (MGIT).
<gallery mode=packed heights=170>
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
File:Mycobacteria Growth Indicator Tube (MGIT) samples in ultraviolet light.jpg|MGIT samples emitting fluorescence in ultraviolet light
</gallery>
Mycobacteriophages
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. Phage therapy can provide an alternate solution to antibiotics, especially in cases of multi drug resistant infections.
Mycosides
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. Different forms of Mycoside C have varying success as a receptor to inactivate mycobacteriophages. Replacement of the gene encoding mycocerosic acid synthase in M. bovis prevents formation of mycosides.