Mechanisms of Antibiotic Tolerance in Mycobacterium avium Complex: Lessons From Related Mycobacteria

Abstract

Mycobacterium avium complex (MAC) species are the most commonly isolated nontuberculous mycobacteria to cause pulmonary infections worldwide. The lengthy and complicated therapy required to cure lung disease due to MAC is at least in part due to the phenomenon of antibiotic tolerance. In this review, we will define antibiotic tolerance and contrast it with persistence and antibiotic resistance. We will discuss physiologically relevant stress conditions that induce altered metabolism and antibiotic tolerance in mycobacteria. Next, we will review general molecular mechanisms underlying bacterial antibiotic tolerance, particularly those described for MAC and related mycobacteria, including Mycobacterium tuberculosis, with a focus on genes containing significant sequence homology in MAC. An improved understanding of antibiotic tolerance mechanisms can lay the foundation for novel approaches to target antibiotic-tolerant mycobacteria, with the goal of shortening the duration of curative treatment and improving survival in patients with MAC.

InMycobacterium abscessus, the stringent factor Rel regulates metabolism, but is not the only (p)ppGpp synthase

“…Mab is notorious for having resistance to many clinical antibiotics and expressing many antibiotic resistance genes (64, 76, 77) which is why it is such a problematic pathogen for cystic fibrosis patients (78). Studies in Mtb show that the Rel-mediated stringent response activates tolerance to at least some antibiotics in that pathogen (11), and it is natural to assume that this would also hold true for Mtb ’s close relatives (79); however, our data in Mab show that antibiotic tolerance in Non-tuberculous Mycobacteria (NTMs) can be regulated differently. The environmental niche of most NTMs is the soil and water systems (80), whereas Mtb lives exclusively in human tissues.…”

Comparative Genomics of Mycobacterium avium Complex Reveals Signatures of Environment-Specific Adaptation and Community Acquisition

“…Both pulmonary and disseminated MAC infections are notoriously refractory to antibiotic treatment ( 5 , 6 ). Along with having innate resistance to entire classes of antibiotics, NTM can acquire antibiotic resistance via mutation and, less commonly, through HGT ( 51 – 53 ). These factors usually necessitate the adoption of lengthy multidrug treatment regimens involving some combination of macrolides, aminoglycosides, rifampin, and ethambutol ( 54 , 55 ).…”

Emerging MDR-Mycobacterium avium subsp. avium in house-reared domestic birds as the first report in Egypt

“…The inh A gene encodes for the enoyl acyl reductase which is involved in the mycolic acid synthesis that is responsible for the isoniazid resistance [ 58 ]. Briefly, the existence of multidrug resistance in the M. avium complex is attributed to several factors including 1-The intrinsic resistance due to the complex thick cell wall and the presence of mycolic acid, 2-The presence of specific antimicrobial resistance genes, and 3-Mutations that takes place in certain genes such as rps L and rpo B genes that adversely affect the activity of the antimicrobial agents [ 59 ].…”