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Vol 53(2019) N 4 p. 596-605; DOI 10.1134/S0026893319040113 Full Text

A. Shaheen1,2, W.A. Afridi1, S. Mahboob2, M. Sana1, N. Zeeshan2, F. Ismat1, O. Mirza3, M. Iqbal1, M. Rahman1*,**

Reserpine Is the New Addition into the Repertoire of AcrB Efflux Pump Inhibitors

1Drug Discovery and Structural Biology group, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, 44000 Pakistan
2Department of Biochemistry and Biotechnology, University of Gujrat, Hafiz Hay at Campus, Gujrat, 50700 Pakistan
3Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 1165 Denmark

*moazur.rahman@fulbrightmail.org
**moaz@nibge.org
Received - 2018-07-09; Revised - 2018-12-15; Accepted - 2019-01-10

Acriflavine resistance protein B (AcrB) serves as prototype for multidrug resistance (MDR) efflux transporters of resistance nodulation division (RND) superfamily. AcrB has been proven as potential drug target with many synthetic and natural inhibitors have been identified such as those belonging to pyranopyridine, naphthamide and pimozide classes. The plant derived alkaloid inhibitors represented by reserpine has been found to inhibit both ATP binding cassette and major facilitator efflux transporters. In this study we report the reserpine induced inhibition of RND transporter AcrB. The preliminary docking analysis hints that reserpine shares its binding site with ciprofloxacin, a known substrate of AcrB and could possibly act as competitive inhibitor. For in vitro validation, AcrB from Salmonella typhi was cloned under the control of tac promoter and resulting vector was introduced into E. coli C41(DE3). Under autoinduced conditions, cells overexpressing AcrB transporter were subjected to combined dose of ciprofloxacin and reserpine. The combined exposure resulted in enhanced ciprofloxacin-induced growth inhibition of cells expressing AcrB transporter as compared to control cells transformed with vector of backbone sequence. Time kill analysis further confirmed these findings. To the best of our knowledge, this is first study to show that exposure to reserpine induces inhibition of AcrB. The assay developed in this study allows simple and reproducible detection of substrate/inhibitor effects upon AcrB and related efflux transporters.

acriflavine resistance protein, resistance nodulation division transporter, reserpine, ciprofloxacin, multidrug resistance, Salmonella typhi



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