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Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide and other drugs in M. tuberculosis

Jiayun Liu, Wanliang Shi, Shuo Zhang, Gail Cassell, Dmitry Maslov, Kirill Shur, Olga Bekker, Valery Danilenko, Xiaoke Hao, Ying Zhang
doi: https://doi.org/10.1101/249102
Jiayun Liu
Xijing Hospital, Fourth Military Medical University;
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Wanliang Shi
Johns Hopkins University;
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Shuo Zhang
Johns Hopkins University;
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Gail Cassell
Harvard Medical School;
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Dmitry Maslov
Vavilov Institute of General Genetics
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Kirill Shur
Vavilov Institute of General Genetics
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Olga Bekker
Vavilov Institute of General Genetics
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Valery Danilenko
Vavilov Institute of General Genetics
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Xiaoke Hao
Xijing Hospital, Fourth Military Medical University;
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Ying Zhang
Johns Hopkins University;
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  • For correspondence: yzhang@jhsph.edu
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Abstract

Although drug resistance in M. tuberculosis is mainly caused by mutations in drug activating enzymes or drug targets, there is increasing interest in possible role of efflux in causing drug resistance. Previously, efflux genes are shown upregulated upon drug exposure or implicated in drug resistance in overexpression studies, but the role of mutations in efflux pumps identified in clinical isolates in causing drug resistance is unknown. Here we investigated the role of mutations in efflux pump Rv1258c (Tap) from clinical isolates in causing drug resistance in M. tuberculosis by constructing point mutations V219A, S292L in Rv1258c in the chromosome of M. tuberculosis and assessed drug susceptibility of the constructed mutants. Interestingly, V219A, S292L point mutations caused clinically relevant drug resistance to pyrazinamide (PZA), isoniazid (INH), and streptomycin (SM), but not to other drugs in M. tuberculosis. While V219A point mutation conferred a low level resistance, the S292L mutation caused a higher level of resistance. Efflux inhibitor piperine inhibited INH and PZA resistance in the S292L mutant but not in the V219A mutant. S292L mutant had higher efflux activity for pyrazinoic acid (the active form of PZA) than the parent strain. We conclude that point mutations in the efflux pump Rv1258c in clinical isolates can confer clinically relevant drug resistance including PZA and could explain some previously unaccounted drug resistance in clinical strains. Future studies need to take efflux mutations into consideration for improved detection of drug resistance in M. tuberculosis and address their role in affecting treatment outcome in vivo.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 17, 2018.
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Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide and other drugs in M. tuberculosis
Jiayun Liu, Wanliang Shi, Shuo Zhang, Gail Cassell, Dmitry Maslov, Kirill Shur, Olga Bekker, Valery Danilenko, Xiaoke Hao, Ying Zhang
bioRxiv 249102; doi: https://doi.org/10.1101/249102
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Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide and other drugs in M. tuberculosis
Jiayun Liu, Wanliang Shi, Shuo Zhang, Gail Cassell, Dmitry Maslov, Kirill Shur, Olga Bekker, Valery Danilenko, Xiaoke Hao, Ying Zhang
bioRxiv 249102; doi: https://doi.org/10.1101/249102

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