Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide and other drugs in M. tuberculosis
| Autor: | K. V. Shur, Shuo Zhang, Jiayun Liu, Ying Zhang, D. A. Maslov, Valery N. Danilenko, Wanliang Shi, Olga B. Bekker, Gail Cassell, Xiaoke Hao |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Drug
0303 health sciences Mutation 030306 microbiology business.industry media_common.quotation_subject Point mutation Drug resistance Pharmacology Pyrazinamide medicine.disease_cause 3. Good health 03 medical and health sciences chemistry.chemical_compound Pyrazinoic acid chemistry Streptomycin medicine Efflux business 030304 developmental biology medicine.drug media_common |
| DOI: | 10.1101/249102 |
| Popis: | Although drug resistance inM. tuberculosisis 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 inM. tuberculosisby constructing point mutations V219A, S292L in Rv1258c in the chromosome ofM. tuberculosisand 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 inM. 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 inM. tuberculosisand address their role in affecting treatment outcome in vivo. |
| Databáze: | OpenAIRE |
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