Abstract
Simple SummaryRecently, there has been a considerable rise in infections caused by nontuberculous mycobacteria (NTM). These mycobacteria, which comprise a large and diverse range of species, have developed resistance to most conventional antibiotics, rendering their treatments unsatisfactory. This review summarizes the mechanisms and strategies adopted by NTMs to evade the action of antimicrobial drugs and techniques that can be used to develop better therapies against them. We also suggest some ways to accelerate the drug development pipeline by utilizing a combination of computational, laboratory and animal testing methods.The genus Mycobacteria comprises a multitude of species known to cause serious disease in humans, including Mycobacterium tuberculosis and M. leprae, the responsible agents for tuberculosis and leprosy, respectively. In addition, there is a worldwide spike in the number of infections caused by a mixed group of species such as the M. avium, M. abscessus and M. ulcerans complexes, collectively called nontuberculous mycobacteria (NTMs). The situation is forecasted to worsen because, like tuberculosis, NTMs either naturally possess or are developing high resistance against conventional antibiotics. It is, therefore, important to implement and develop models that allow us to effectively examine the fundamental questions of NTM virulence, as well as to apply them for the discovery of new and improved therapies. This literature review will focus on the known molecular mechanisms behind drug resistance in NTM and the current models that may be used to test new effective antimicrobial therapies.
Highlights
The genus Mycobacteria comprises a multitude of species known to cause serious disease in humans, including Mycobacterium tuberculosis and M. leprae, the responsible agents for tuberculosis and leprosy, respectively
M. avium complex and M. abscessus [6,7], but NTMs can cause skin and soft tissue infections (e.g., M. marinum infection and Buruli ulcer caused by M. ulcerans), lymphadenitis in immunocompromised children, and even invasive disseminated disease eventually leading to death
There is controversy about the role of in vitro susceptibility testing for NTM diseases. This is mainly due to the unpredictable correlation between in vitro and clinical outcomes: correlation is poor for M. abscessus and M. simiae, while it is reasonably satisfactory for M. kansasii, M. marinum and M. fortuitum, and for other species such as M. avium complex, the correlation holds good only for certain drugs like macrolides, but not for others [4]
Summary
Mycobacteria are a large group of non-motile, rod-shaped bacteria that tend to grow mold-like pellicles on liquid culture media. There has been a considerable increase in the number of reported NTM related diseases, including respiratory infections caused by various strains from the M. avium complex, M. kansasii and M. abscessus [25] This is partly because of the awareness of the symptoms caused by these infections and improvements in detection techniques, and because of an increase in the number of susceptible individuals and that NTM can form biofilms in common household and hospital sources of infection (such as showerheads, faucets, water distribution systems, plumbing systems, etc.) [26,27]. The major NTM that is infecting such individuals suffering from chronic diseases like cystic fibrosis is M. abscessus, which is a rapidly growing, intrinsically multidrug-resistant species [30] These infections are often impossible to treat despite prolonged antibiotic therapy, and the therapy may even be contraindicated with lung transplantation, leaving no effective options for treatment [31]. A better understanding of the underlying mechanisms behind this drug resistance by improving the available models to study their infection could significantly help in accelerating the drug discovery process
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