Reserpine Is the New Addition into the Repertoire of AcrB Efflux Pump Inhibitors
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Reserpine Is the New Addition into the Repertoire of AcrB Efflux Pump Inhibitors. / Shaheen, A; Afridi, W A; Mahboob, S; Sana, M; Zeeshan, N; Ismat, F; Mirza, O; Iqbal, M; Rahman, M.
I: Molecular Biology, Bind 53, Nr. 4, 10.08.2019, s. 674-684.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt
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TY - JOUR
T1 - Reserpine Is the New Addition into the Repertoire of AcrB Efflux Pump Inhibitors
AU - Shaheen, A
AU - Afridi, W A
AU - Mahboob, S
AU - Sana, M
AU - Zeeshan, N
AU - Ismat, F
AU - Mirza, O
AU - Iqbal, M
AU - Rahman, M
N1 - Erratum: 10.1134/S0026893319090012
PY - 2019/8/10
Y1 - 2019/8/10
N2 - 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.
AB - 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.
U2 - 10.1134/S0026893319040113
DO - 10.1134/S0026893319040113
M3 - Journal article
C2 - 31397441
VL - 53
SP - 674
EP - 684
JO - Molekulyarnaya Biologiya
JF - Molekulyarnaya Biologiya
SN - 0026-8933
IS - 4
ER -
ID: 225692428