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A Test System for in vitro Screening Antimycobacterial Drug Candidates for MmpS5-MmpL5 Mediated Resistance

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Abstract

Emergence of drug-resistance to antituberculosis agents is a global challenge that requires development of novel drugs, active against resistant Mycobacterium tuberculosis strains. One of the tasks of drug development is to determine the mechanism of resistance of the pathogen to the drug candidate. The mycobacterial MmpS5-MmpL5 efflux system can provide resistance to a wide range of antibiotics, including bedaquiline, clofazimine, thiacetazones, azoles, and imidazo[1,2-b][1,2,4,5]tetrazines. We were able to construct a recombinant M. smegmatis Δmmp5 strain, which carries a deletion within the mmpS5-mmpL5 operon and is hypersensitive to imidazo[1,2-b][1,2,4,5]tetrazines. Comparing the sensitivity of M. smegmatis mc2 155 and M. smegmatis Δmmp5 to candidate antimycobacterials can be used as a test system for determining the possible role of the MmpS5-MmpL5 efflux system in developing drug resistance at early screening stages.

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ACKNOWLEDGMENTS

We are grateful to V.N. Charushin and G.L. Rusinov for the provided compounds of the imidazo[1,2-b][1,2,4, 5]tetrazines class.

Funding

This study was supported by a grant from the Russian Science Foundation (RSF grant no. 17-75-20060, “Search for Biotargets of Azolo[1,2,4,5]tetrazine-Based Antituberculosis Drug-Candidates”).

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Authors and Affiliations

  1. Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333, Moscow, Russia

    K. V. Shur, S. G. Frolova, N. I. Akimova, V. N. Danilenko & D. A. Maslov

  2. Moscow Institute of Physics and Technology (State University), 141701, Dolgoprudny, Moscow oblast, Russia

    S. G. Frolova

Authors
  1. K. V. Shur
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  2. S. G. Frolova
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  3. N. I. Akimova
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  4. V. N. Danilenko
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  5. D. A. Maslov
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Corresponding author

Correspondence to D. A. Maslov.

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The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.

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Shur, K.V., Frolova, S.G., Akimova, N.I. et al. A Test System for in vitro Screening Antimycobacterial Drug Candidates for MmpS5-MmpL5 Mediated Resistance. Russ J Genet 57, 114–116 (2021). https://doi.org/10.1134/S1022795421010154

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  • DOI: https://doi.org/10.1134/S1022795421010154

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