Abstract
Drug resistance in Mycobacterium leprae is assumed to be due to genetic alterations in the drug targets and reduced cell wall permeability. However, as observed in Mycobacterium tuberculosis, drug resistance may also result from the overactivity of efflux systems, which is mostly unexplored. In this perspective, we discuss known efflux pumps involved in M. tuberculosis drug resistance and virulence and investigate similar regions in the genome of M. leprae. In silico analysis reveals that the major M. tuberculosis efflux pumps known to be associated with drug resistance and virulence have been retained during the reductive evolutionary process that M. leprae underwent, e.g., RND superfamily, the ABC transporter BacA, and the MFS P55. However, some are absent (DinF, MATE) while others are derepressed (Mmr, SMR) in M. leprae reflecting the specific environment where M. leprae may live. The occurrence of several multidrug resistance efflux transporters shared between M. leprae and M. tuberculosis reveals potential implications in drug resistance and virulence. The conservation of the described efflux systems in M. leprae upon genome reduction indicates that these systems are potentially required for its intracellular survival and lifestyle. They potentially are involved in M. leprae drug resistance, which could hamper leprosy treatment success. Studying M. leprae efflux pumps as new drug targets is useful for future leprosy therapeutics, enhancing the global efforts to eradicate endemic leprosy, and prevent the emergence of drug resistance in afflicted countries.
Highlights
Leprosy and tuberculosis are public health threatening infectious diseases with similar problems of ongoing human-to-human transmission, inherent drug resistance to several antimicrobial agents, propensity to develop resistance to antimycobacterial drugs, and virulence (Singh et al, 2016; Dheda et al, 2017)
Multidrug resistance efflux pumps are ubiquitous in nature
Some efflux pumps exhibit a dual role in M. tuberculosis contributing to both drug resistance and virulence
Summary
Leprosy and tuberculosis are public health threatening infectious diseases with similar problems of ongoing human-to-human transmission, inherent drug resistance to several antimicrobial agents, propensity to develop resistance to antimycobacterial drugs, and virulence (Singh et al, 2016; Dheda et al, 2017). The induction of efflux systems in the presence of inducers such as antimicrobials or host factors during infection promote a low-level resistance phenotype that allows the bacteria to survive during prolonged periods in the presence of drugs contributing for the development and stabilization of resistant phenotypes (Machado et al, 2012; Schmalstieg et al, 2012). The shift toward lower G+C contents and smaller genomes in obligate pathogenic mycobacteria seems to occur in response to environmental adaptation where they encounter low selective pressure (Mann and Chen, 2010) In this context some genes became inactivated, as they are not required in these highly specialized niches meeting the theoretical principles of Morris, Lenski, and Zinser’s Black Queen Hypothesis for the symbiotic reductive genome evolution of microorganisms (Morris et al, 2012), applied to a bacterium and his long-lasting and almost exclusive host—the human being. This can be viewed as the time when the host decides that he no longer wants to maintain this intimate relation and starts antibiotic treatment with the assistance of his clinician and the health system
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