Non-tuberculous Mycobacterial Disease

''Mycobacterium'' is a genus of over 190 species 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' mold-like colony surfaces. Since this genus has cell walls with Gram-positive and Gram-negative features, acid-fast staining is used to emphasize their resistance to acids, compared to other cell types.

Metabolism and Morphology

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. 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.

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 25-45°C.

Most ''Mycobacterium'' species, including most clinically relevant species, can be cultured in blood agar. 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.

Pathogenicity

''Mycobacterium tuberculosis'' can remain latent in human hosts, decades after an initial infection, to continue infecting others. 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.

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 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.

Genomics

Comparative analyses of mycobacterial genomes have identified several conserved indels and signature proteins that are uniquely found in all sequenced species from the genus ''Mycobacterium''. Additionally, 14 proteins are found only in the species from the genera ''Mycobacterium'' and ''Nocardia'', suggesting that these two genera are closely related.

The genomes of some mycobacteria are quite large, such as ''M. vulneris'' encoding 6,653 proteins, larger than the ~6000 proteins of eukaryotic yeast.

Species

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" 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 Mycobacterium tuberculosis complex ( tuberculosis), Mycobacterium avium complex ( mycobacterium avium-intracellulare infection), ''M. leprae'' and '' M. lepromatosis'' ( leprosy), and Mycobacterium abscessus ( chronic lung infection).

Microbiologist Enrico Tortoli has constructed a phylogentic 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:

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 Florescent 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.

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 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.

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.

References

External links

Bacterial and Viral Bioinformatics Resource Center
Genomes, proteins, epitopes, and pathways of mycobacteria

Merck Manual - Mycobacteria

Mycobrowser
Genomic and proteomic database for pathogenic mycobacteria





TB Structural Genomics Consortium

{{Taxonbar, from=Q194309

Acid-fast bacilli
Tuberculosis
Bacteriology
Bacterial diseases
Bacteria genera
Mycobacteria
Pathogenic bacteria
Infectious causes of cancer