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Abstract
The incidence and prevalence of non-tuberculous mycobacterial (NTM) infections have been increasing worldwide and lately led to an emerging public health problem. Among rapidly growing NTM, Mycobacterium abscessus is the most pathogenic and drug resistant opportunistic germ, responsible for disease manifestations ranging from “curable” skin infections to only “manageable” pulmonary disease. Challenges in M. abscessus treatment stem from the bacteria’s high-level innate resistance and comprise long, costly and non-standardized administration of antimicrobial agents, poor treatment outcomes often related to adverse effects and drug toxicities, and high relapse rates. Drug resistance in M. abscessus is conferred by an assortment of mechanisms. Clinically acquired drug resistance is normally conferred by mutations in the target genes. Intrinsic resistance is attributed to low permeability of M. abscessus cell envelope as well as to (multi)drug export systems. However, expression of numerous enzymes by M. abscessus, which can modify either the drug-target or the drug itself, is the key factor for the pathogen’s phenomenal resistance to most classes of antibiotics used for treatment of other moderate to severe infectious diseases, like macrolides, aminoglycosides, rifamycins, β-lactams and tetracyclines. In 2009, when M. abscessus genome sequence became available, several research groups worldwide started studying M. abscessus antibiotic resistance mechanisms. At first, lack of tools for M. abscessus genetic manipulation severely delayed research endeavors. Nevertheless, the last 5 years, significant progress has been made towards the development of conditional expression and homologous recombination systems for M. abscessus. As a result of recent research efforts, an erythromycin ribosome methyltransferase, two aminoglycoside acetyltransferases, an aminoglycoside phosphotransferase, a rifamycin ADP-ribosyltransferase, a β-lactamase and a monooxygenase were identified to frame the complex and multifaceted intrinsic resistome of M. abscessus, which clearly contributes to complications in treatment of this highly resistant pathogen. Better knowledge of the underlying mechanisms of drug resistance in M. abscessus could improve selection of more effective chemotherapeutic regimen and promote development of novel antimicrobials which can overwhelm the existing resistance mechanisms. This article reviews the currently elucidated molecular mechanisms of antibiotic resistance in M. abscessus, with a focus on its drug-target-modifying and drug-modifying enzymes.
Highlights
Non-tuberculous mycobacteria (NTM) encompass all species of mycobacteria that do not cause tuberculosis (TB) or leprosy (Lee et al, 2015)
We provide an up-to-date overview of the main molecular mechanisms of antibiotic resistance in M. abscessus with a focus on the drugtarget-modifying or drug-modifying enzymes and discuss the potential impact on clinical treatment
A WhiB7 like protein encoded by MAB_3508c was recently uncovered as a multi-drug inducible transcriptional regulator that modulates the expression of genes conferring aminoglycoside and macrolide resistance in M. abscessus
Summary
Non-tuberculous mycobacteria (NTM) encompass all species of mycobacteria that do not cause tuberculosis (TB) or leprosy (Lee et al, 2015). A recent whole genome analysis of more than 1000 M. abscessus clinical isolates from different geographical locations, revealed the presence of genetically clustered strains in patients. Mycobacterium abscessus is an opportunistic pathogen, ubiquitous in the environment, that often causes infections in humans with compromised natural defenses such as patients with cystic fibrosis or other chronic lung diseases (Sanguinetti et al, 2001; Brown-Elliott and Wallace, 2002; Howard, 2006; Griffith et al, 2007). Treatment of M. abscessus pulmonary disease as recommended by the British Thoracic Society involves administration of a multi-drug regimen encompassing intravenous antibiotics - amikacin, tigecycline, and imipenem along with an oral macrolide (clarithromycin or azithromycin) for clinical isolates susceptible to macrolides, during the initial treatment phase. Mechanisms underpinning intrinsic drug resistance of M. abscessus are multi-fold and fall into two main groups: first, the presence of a highly impermeable cell envelope
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