RESEARCH ARTICLE


Constraints of Drug Resistance in Mycobacterium tuberculosis - Prospects for Pharmacological Reversion of Susceptibility to Antibiotics



Aleksandr I. Ilin*, 1, Murat E. Kulmanov1, Ilya S. Korotetskiy1, Marina V. Lankina1, Gulshara K. Akhmetova1, Sergey V. Shvidko1, Oleg N. Reva*, 2
1 Scientific Center for Anti-Infectious Drugs (SCAID), Almaty, Kazakhstan
2 Centre for Computational Biology and Bioinformatics (CBCB), Department of Biochemistry, University of Pretoria, Pretoria, South Africa


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© 2017 Ilin et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to these authors at the Centre for Bioinformatics and Computational Biology, Department of Biochemistry, University of Pretoria, Hillcrest, Lynnwood Rd, Pretoria 0002, South Africa; Tel: +27-12-420-5810; Fax: +27-12-420-5800; E-mail: oleg.reva@up.ac.za;
Scientific Center for Anti-Infectious Drugs (SCAID), 75V Al-Farabi Ave, Almaty 050060, Kazakhstan; Tel: +8-727-266-4832; E-mail: ilin_ai@mail.ru


Abstract

Emergence of multidrug resistant strains of Mycobacterium tuberculosis (MDR-TB) threatens humanity. This problem was complicated by the crisis in development of new anti-tuberculosis antibiotics. Induced reversion of drug resistance seems promising to overcome the problem. Successful clinical trial of a new anti-tuberculosis nanomolecular complex FS-1 has demonstrated prospectively of this approach in combating MDR-TB. Several clinical MDR-TB cultures were isolated from sputum samples prior and in the process of the clinical trial. Every isolate was tested for susceptibility to antibiotics and then they were sequenced for comparative genomics. It was found that the treatment with FS-1 caused an increase in the number of antibiotic susceptible strains among Mtb isolates that was associated with a general increase of genetic heterogeneity of the isolates. Observed impairing of phthiocerol dimycocerosate biosynthesis by disruptive mutations in ppsACD subunits indicated a possible virulence remission for the sake of persistence. It was hypothesized that the FS-1 treatment eradicated the most drug resistant Mtb variants from the population by aggravating the fitness cost of drug resistance mutations. Analysis of distribution of these mutations in the global Mtb population revealed that many of them were incompatible with each other and dependent on allelic states of many other polymorphic loci. The latter discovery may explain the negative correlation between the genetic heterogeneity of the population and the level of drug tolerance. To the best of our knowledge, this work was the first experimental confirmation of the drug induced antibiotic resistance reversion by the induced synergy mechanism that previously was predicted theoretically.

Keywords: Tuberculosis, Drug resistance reversion, NGS, Comparative genomics, Variant calling, Single nucleotide polymorphism.