Mycobacterium abscessus

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1. Classification

a. Higher order taxa

Higher-order taxa: Bacteria; Actinobacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae Species: Mycobacterium abscessus

2. Description and significance

Mycobacterium abscessus (M. abscessus) is a species complex with three distinct subtypes, known to cause infection predominantly in the lungs, especially among those with pre-existing lung conditions such as cystic fibrosis (Bryant, 2016). Much is known about the morphology and physiology of the bacteria, such as its optimal growth conditions, cell structure, and colony shape and color. However, less is known about how M. abscessus establishes infection in the body (pathogenesis) and how it is transmitted in epidemic scenarios that are currently occurring in certain parts of the world, recently in Shanghai, China (Luo, 2016). Treatment of M. abscessus infections has become an increasingly popular research field due to the pressing concerns of epidemics and the damage these infections cause to immunocompromised individuals (Kwak, 2019, Luthra, 2018, Dupont, 2017).

3. Genome structure

The M. abscessus genome, first sequenced in 2009, has a 5067 kb circular chromosome with a 64% GC content and a 23 kb mercury resistance plasmid with a 68% GC content. It has an 81 kb prophage and has five insertion sequences in its genome, fewer than other sequenced mycobacteria (Ripoll, 2009). Its genome codes for many drug modifying enzymes, such as beta-lactamase, monooxygenases, and aminoglycoside phosphotransferases, that can break down antibiotics used in infection treatment (Ripoll, 2009). Most of these antibiotic resistance enzymes are from other mycobacterial species except for the Ambler class A beta-lactamase, which is closely related to beta-lactamase found in Pseudomonas luteola, a Gram-negative bacteria (Ripoll, 2009). Genes encoding proteins useful for surviving in a host (such as MgtC, MsrA, phospholipase C) were acquired through horizontal gene transfer (Ripoll, 2009).

4. Cell structure

M. abscessus has a typical mycobacterium envelope structure: a plasma membrane and an outer membrane flanking a peptidoglycan cell wall (Gutierrez, 2018). Mycolic acids are found in the cell wall, making it waxy and hydrophobic. The outer layer contains glycopeptidolipids, which may affect the pathogenicity of certain strains, as glycopeptidolipid content has been shown to affect biofilm formation, cord-forming, and macrophage apoptosis. (Gutierrez, 2018).

5. Metabolic processes

M. abscessus has a urease enzyme and a highly efficient, thermostable catalase enzyme (Bhalla, 2018). The former allows it to hydrolyze urea, while the latter allows it to catalyze hydrogen peroxide at temperatures up to 68°C . It is not capable of nitrate reduction and cannot use citrate as a sole carbon source (Bhalla, 2018). The metabolic processes of M. abscessus vary based on its environment. It has been found that in biofilms or anaerobic environments, there is an increase in citrate cycle and oxidative phosphorylation metabolism (Rojony, 2020). To survive in low nutrient environments, M. abscessus increases its rate of fatty acid metabolism and peptidoglycan synthesis, both of which are involved in membrane modification (Rojony, 2020).

6. Ecology

M. abscessus is considered a saprophyte, meaning that when it is not infecting a host, it lives in soil or water and feeds on decaying organic matter (Howard, 2000). Like other nontuberculous bacteria, it can form biofilms and survive on limited nutrients (Lopeman, 2019). The ability to form biofilms gives M. abscessus the ability to withstand most environments, allowing it to grow close to human populations (Lopeman, 2019).

7. Pathology

M. abscessus infection is commonly found to cause pulmonary disease, but M. abscessus can also cause skin, soft tissue, and central nervous system infection (Lee, 2015). Patients that already have a respiratory disease, such as cystic fibrosis or tuberculosis, are more susceptible to infection. Those infected with non-tuberculous mycobacteria such as M. abscessus are more likely to experience a decline in lung health if they are young, male, or have bronchiectasis (Lee, 2013). Younger patients or those with more severe cystic fibrosis tend to be infected by M. abscessus more often, which may be due to the intravenous antimicrobial therapy they undergo (Catherinot, 2013). Two primary sources for human infection are contaminated water and unsanitary hospital settings (Lee, 2015), and the modes of transmission are fomites and aerosols (Bryant, 2016). Drugs that are effective for slow-growing mycobacteria species like M. tuberculosis are not effective for fast-growing mycobacteria species like M. abscessus (Chopra, 2011). M. abscessus has two variants: rough (R) and smooth (S). The R variant is more virulent than the S variant and appears to be responsible for the majority of M. abscessus infection (Bernut, 2014). The pathophysiology of M. abscessus has been well studied. The primary means of infection occurs when macrophages engulf the bacteria. (Bernut, 2014). Additional macrophage recruitment to the site of infection forms granulomas and infected macrophages travel to the central nervous system (CNS). When infected macrophages inevitably die via apoptosis, this releases the bacteria and allows for cord formation in the CNS (Bernut, 2014). These cord structures are too large to be phagocytosed by macrophages and neutrophils, leading to uncontrolled bacterial replication. Uncontrolled replication in these cords leads to abscess formation, tissue damage, and eventually death if left untreated. Understanding how cord formation is a way in which M. abscessus evades the body’s immune system has led to a consideration of inhibition of cord formation as a therapeutic measure for infection (Bernut, 2014).

8. Current Research

Mycobacterium abscessus can cause lung infections in susceptible individuals and immunocompromised people (Bryant, 2016). Current research has been focused on finding an effective treatment for M. abscessus pulmonary infection and the side effects of M. abscessus pulmonary infection treatment. Until now, the only viable treatment was to administer multiple antibiotics for a long time (Chen, 2019). One study found that a combination of drugs like azithromycin, amikacin, or imipenem was successful in the treatment of M. abscessus infection, yet they also resulted in adverse effects in patients (Kwak, 2019). Clarithromycin, azithromycin, amikacin, imipenem, and linezolid are reported to cause gastrointestinal distress and other adverse events like ototoxicity and nephrotoxicity, which are specific to amikacin. Treatment success rate improves when the antibiotics are used in conjunction with each other; however, the total incidence of adverse effects also increased in some cases (Chen, 2019). Because of the adverse effects of the current treatments, some researchers have focused on repurposing drugs to treat M. abscessus infection. For example, bedaquiline, a drug used for the treatment of tuberculosis, is as effective against M. abscessus infection as imipenem in a zebrafish model. Bedaquiline is an ATP synthase inhibitor, decreasing ATP levels found in M. abscessus upon treatment (Dupont, 2017). Infected zebrafish treated with this drug displayed an increase in their survival. Most significantly, bedaquiline was found to be effective against all three subspecies of M. abscessus, which commonly react differently to a specific treatment (Dupont, 2017). After originating in the United Kingdom in 1978, the outbreak of M. abscessus and its multidrug-resistance has become an important research area. The low permeability of the M. abscessus cell envelope and its multidrug export system confer innate antibiotic resistance to the bacterium. However, its ability to modify the drug-target or the drug itself by using native enzymes account for a large majority of its resistance to most classes of antibiotics such as macrolides, aminoglycosides, rifamycins, β-lactams, and tetracyclines (Luthra, 2018). Because M. abscessus has an innate resistance to a variety of antibiotics, research has focused on understanding the genetic basis of antibiotic resistance of M. abscessus. Much of the current research regarding antibiotic resistance in M. abscessus has been focused on which drugs work best on strains with particular antibiotic resistance. For example, rifabutin has been seen as more effective against most clinical M. abscessus strains, including the prevalent clarithromycin-resistant strains (Ye, 2018). Furthermore, some M. abscessus strains are resistant to the antibiotic linezolid (LZD), and these strains are best treated by targeting efflux pumps which allow for the uptake of LZD rather than targeting mutations or modifications to LZD target sites (Ye, 2018). Research has also focused on how certain strains of M. abscessus develop antibiotic resistance. For example, lipoprotein glycosylation by protein O-mannosyltransferase has been found to contribute to low cell envelope permeability, which decreases antibiotic uptake and bacterial destruction by these antibiotics (Becker, 2017). This finding explains how certain antibiotics such as β-lactams can affect mutated bacteria with lipoprotein glycosylation deficiency (Becker, 2017). Additionally, streptomycin-resistant strains of M. abscessus were discovered to carry a MAB_2385 gene that directly confers resistance (Molin, 2018). M. abscessus strains that did not have this resistance could become streptomycin-resistant by transforming this gene (Molin, 2018).

9. References

[1] Becker, K., Haldimann, K., Selchow, P., Reinau, L. M., Molin, M. D., Sander, P. (2017). Lipoprotein Glycosylation by Protein-O-Mannosyltransferase (MAB_1122c) Contributes to Low Cell Envelope Permeability and Antibiotic Resistance of Mycobacterium abscessus. Front. Microbiol. 8: 2123.

[2] Bernut, A., Hermann, J.L., Kissa, K., Dubremetz, J.F., Gaillard, J.L., Lutfalla, G., Kremer, L. (2014). Mycobacterium abscessus cording prevents phagocytosis and promotes abscess formation. Proc Natl Acad Sci U S A 111 (10): e943-952.

[3] Bhalla, G. S., Sarao, M. S., Kalra, D., Bandyopadhyay, K., & John, A. R. (2018). Methods of phenotypic identification of non-tuberculous mycobacteria. Practical laboratory medicine, 12, e00107.]

[4] Bryant, J. M., Grogono, D. M., Rodriguez-Rincon, D., Everall, I., Brown, K. P., Moreno, P., … Floto, R. A. (2016). Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium. Science 354 (6313): 751–757.

[5] Catherinot, E., Roux, A. L., Vibet, M. A., Bellis, G., Ravilly, S., Lemonnier, L., … Gaillard, J. L. (2013). Mycobacterium avium and Mycobacterium abscessus complex target distinct cystic fibrosis patient subpopulations. Journal of Cystic Fibrosis 12 (1): 74-80.

[6] Chen, J., Zhao, L., Mao, Y., Ye, M., Guo, Q., Zhang, Y., … Chu, H. (2019). Clinical efficacy and adverse effects of antibiotics used to treat Mycobacterium abscessus pulmonary disease. Front. Microbiol. 10:1977.

[7] Chopra, S., Matsuyama, K., Hutson, C., Madrid, P. (2011). Identification of antimicrobial activity among FDA-approved drugs for combating Mycobacterium abscessus and Mycobacterium chelonae. Journal of Antimicrobial Chemotherapy 66 (7): 1533–1536.

[8] Dupont, C., Viljoen, A., Thomas, S., Roquet-Banères, F., Herrmann, J. L., Pethe, K., Kremer, L. (2017). Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish. Antimicrobial agents and chemotherapy 61 (11): e01225-17.

[9] Gutiérrez, A. V., Viljoen, A., Ghigo, E., Herrmann, J. L., Kremer, L. (2018). Glycopeptidolipids, a Double-Edged Sword of the Mycobacterium abscessus Complex. Front. Microbiol. 9: 1145.

[10] Howard, S. T., Byrd, T. F. (2000). The rapidly growing mycobacteria: saprophytes and parasites. Microbes and infection 2 (15): 1845–1853.

[11] Kwak, N., Dalcolmo, M. P., Daley, C. L., Eather, G., Gayoso, R., Hasegawa, N., … Yim, J. (2019). Mycobacterium abscessus pulmonary disease: individual patient data meta-analysis. Eur. Respir. J. 54 (1): 1801991.

[12] Lee, M. R., Sheng, W. H., Hung, C. C., Yu, C. J., Lee, L. N., Hsueh, P. R. (2015). Mycobacterium abscessus Complex Infections in Humans. Emerging infectious diseases 21 (9): 1638–1646.

[13] Lee, M. R., Yang, C. Y., Chang, K. P., Keng, L. T., Yen, D. H., Wang, J. Y., …. Yu, C. J. (2013). Factors associated with lung function decline in patients with non-tuberculous mycobacterial pulmonary disease. PLoS One 8 (3): e58214.

[14] Lopeman, R. C., Harrison, J., Desai, M., Cox, J. (2019). Mycobacterium abscessus: Environmental Bacterium Turned Clinical Nightmare. Microorganisms 7 (3): 90.

[15] Luthra, S., Rominski, A., Sander, P. (2018). The role of antibiotic-target-modifying and antibiotic-modifying enzymes in Mycobacterium abscessus drug resistance. Front. Microbiol. 9: 2179.

[16] Luo, L., Li, B., Chu, H., Huang, D., Zhang, Z., Zhang, J., … Xiao, H. (2016). Characterization of Mycobacterium Abscessus Subtypes in Shanghai of China: Drug Sensitivity and Bacterial Epidemicity as well as Clinical Manifestations. Medicine 95 (3): e2338.

[17] Molin, M. D., Gut, M., Rominski, A., Haldimann, K., Becker, K., Sander, P. (2018). Molecular Mechanisms of Intrinsic Streptomycin Resistance in Mycobacterium abscessus. Antimicrob Agents Chemother. 62 (1).

[18] Ripoll, F., Pasek, S., Schenowitz, C., Dossat, C., Barbe, V., Rottman, M., … Gaillard, J. L. (2009). Non-mycobacterial virulence genes in the genome of the emerging pathogen Mycobacterium abscessus. PLoS One 4 (6).

[19] Rojony, R., Danelishvili, L., Campeau, A., Wozniak, J. M., Gonzalez, D. J., Bermudez, L. E. (2020). Exposure of Mycobacterium abscessus to Environmental Stress and Clinically Used Antibiotics Reveals Common Proteome Response among Pathogenic Mycobacteria. Microorganisms 8 (5): 698.

[20] Ye, M., Xu, L., Zou, Y., Li, B., Guo, Q., Zhang, Y., … Chu, H. (2018). Molecular Analysis of Linezolid-Resistant Clinical Isolates of Mycobacterium Abscessus. Antimicrobial Agents and Chemotherapy 63 (2): e01842-18.

Author contributions: E.Y. wrote the Classification section; A.P. wrote the Introduction section; V.S., E.Y. wrote the Genome, Cell Structure, Ecology and Metabolism sections; A.P. wrote the Pathology section; CC.L, P.T., and V.S. wrote the Current Research section; and A.P. edited citations. The whole article was edited and researched by all.

Edited by [Viktoriya Skidanova], student of Jennifer Bhatnagar for BI 311 General Microbiology, 2020, Boston University.