Abstract
Drug induced reversion of antibiotic resistance is a promising way to combat multidrug resistant infections. However, lacking knowledge of mechanisms of drug resistance reversion impedes employing this approach in medicinal therapies. Induction of antibiotic resistance reversion by a new anti-tuberculosis drug FS-1 has been reported. FS-1 was used in this work in combination with standard anti-tuberculosis antibiotics in an experiment on laboratory guinea pigs infected with an extensively drug resistant (XDR) strain Mycobacterium tuberculosis SCAID 187.0. During the experimental trial, genetic changes in the population were analyzed by sequencing of M. tuberculosis isolates followed by variant calling. In total 11 isolates obtained from different groups of infected animals at different stages of disease development and treatment were sequenced. It was found that despite the selective pressure of antibiotics, FS-1 caused a counter-selection of drug resistant variants that speeded up the recovery of the infected animals from XDR tuberculosis. Drug resistance mutations reported in the genome of the initial strain remained intact in more sensitive isolates obtained in this experiment. Variant calling in the sequenced genomes revealed that the drug resistance reversion could be associated with a general increase in genetic heterogeneity of the population of M. tuberculosis. Accumulation of mutations in PpsA and PpsE subunits of phenolpthiocerol polyketide synthase was observed in the isolates treated with FS-1 that may indicate an increase of persisting variants in the population. It was hypothesized that FS-1 caused an active counter-selection of drug resistant variants from the population by aggravating the cumulated fitness cost of the drug resistance mutations. Action of FS-1 on drug resistant bacteria exemplified the theoretically predicted induced synergy mechanism of drug resistance reversion. An experimental model to study the drug resistance reversion phenomenon is hereby introduced.
Highlights
The dilemma of acquired drug resistance by pathogenic bacteria is generally recognized (Tenover, 2001; Morens et al, 2004)
The present study proved the efficacy of the combinatorial treatment of infected animals by conventional anti-tuberculosis antibiotics supplemented with FS-1
Minimal inhibitory concentration (MIC) of FS-1 was identified for the clinical isolate M. tuberculosis Scientific Center for Anti-Infectious Drugs (SCAID) 187 during the first isolation and after 60 days of the combinatorial treatment by complex of anti-tuberculosis antibiotics (CAA)+FS-1
Summary
The dilemma of acquired drug resistance by pathogenic bacteria is generally recognized (Tenover, 2001; Morens et al, 2004). The mechanisms of this phenomenon are not understood and even the terminology has not been well defined In early publications, this term referred to a suppression of antibiotic resistance proteins such as drug efflux pumps and/or beta-lactamases (Reading and Cole, 1977; Rodrigues et al, 2013). This term referred to a suppression of antibiotic resistance proteins such as drug efflux pumps and/or beta-lactamases (Reading and Cole, 1977; Rodrigues et al, 2013) Another definition was given in a recent review by Baym et al (2016), where this phenomenon was considered as an active drug induced counter-selection of resistant variants from populations of pathogens. The idea to aggravate the cumulated fitness cost by supplementary drugs in an effort to combat drug resistance still seems attractive
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