The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

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.

Recent updates on drug resistance in Mycobacterium tuberculosis

“…The evolution of multiple molecular mechanisms in Mtb has allowed the pathogen to cope up with the cytotoxicity of antibiotics and other toxic chemicals and lead to the development of intrinsic drug resistance (Nguyen ; Luthra et al . ). The observed high background of intrinsic resistance limits TB treatment by both existing and new antibiotics.…”

“…The following are the mechanisms contributing to the overall intrinsic drug resistance in Mtb (Nguyen ; Luthra et al . ).…”

“…Two or more of the following Group‐C second‐line agents, that is, ethionamide (or prothionamide), cycloserine (or terizidone), linezolid and clofazimine (Luthra et al . ; Falzon et al ) should be included during the intensive phase of MDR‐TB core regimen, so that the total number of effective second‐line TB drugs is at least four. Bedaquiline or delamanid may be added to the longer MDR‐TB regimen to either replace another second‐line agent or to strengthen it.…”

Repositioning rifamycins for Mycobacterium abscessus lung disease

“…This box summarizes key points contained in the article. drugs [10,27], and even for the few drugs that show potency in vitro there is limited correlation between in vitro drug susceptibility and clinical outcomes [62]. Thus, there is no standard, reliable antibiotic regimen for M. abscessus lung disease [18,63].…”

“…massilienseis the 'ugly duckling', the most difficult to treat with no reliable cure, similar to extremely drug resistant TB. All NTM species and particularly M. abscessus are intrinsically resistant to many drug classes [9][10][11][12]. Among the many factors underlying M. abscessus' natural drug resistance, the pathogen's ability to metabolize most antibiotic classes and convert them to inactive derivatives stands as a key mechanism [10,[13][14][15][16][17].…”