Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/128630
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Type: Journal article
Title: Evaluation of a series of 2-napthamide derivatives as inhibitors of the drug efflux pump AcrB for the reversal of antimicrobial resistance
Author: Wang, Y.
Mowla, R.
Guo, L.
Ogunniyi, A.
Rahman, T.
De Barros Lopes, M.
Ma, S.
Venter, H.
Citation: Bioorganic and Medicinal Chemistry Letters, 2017; 27(4):733-739
Publisher: Elsevier
Issue Date: 2017
ISSN: 0960-894X
1464-3405
Statement of
Responsibility: 
Yinhu Wang, Rumana Mowla, Liwei Guo, Abiodun D. Ogunniyi, Taufiq Rahman, Miguel A. De Barros Lopes, Shutao Ma, Henrietta Venter
Abstract: Drug efflux pumps confer multidrug resistance to dangerous pathogens which makes these pumps important drug targets. We have synthesised a novel series of compounds based on a 2-naphthamide pharmacore aimed at inhibiting the efflux pumps from Gram-negative bacteria. The archeatypical transporter AcrB from Escherichia coli was used as model efflux pump as AcrB is widely conserved throughout Gram-negative organisms. The compounds were tested for their antibacterial action, ability to potentiate the action of antibiotics and for their ability to inhibit Nile Red efflux by AcrB. None of the compounds were antimicrobial against E. coli wild type cells. Most of the compounds were able to inhibit Nile Red efflux indicating that they are substrates of the AcrB efflux pump. Three compounds were able to synergise with antibiotics and reverse resistance in the resistant phenotype. Compound A3, 4-(isopentyloxy)-2-naphthamide, reduced the MICs of erythromycin and chloramphenicol to the MIC levels of the drug sensitive strain that lacks an efflux pump. A3 had no effect on the MIC of the non-substrate rifampicin indicating that this compound acts specifically through the AcrB efflux pump. A3 also does not act through non-specific mechanisms such as outer membrane or inner membrane permeabilisation and is not cytotoxic against mammalian cell lines. Therefore, we have designed and synthesised a novel chemical compound with great potential to further optimisation as inhibitor of drug efflux pumps.
Keywords: 2-Naphthamide; Antimicrobial resistance; Efflux pump inhibitor; Drug efflux pump; AcrB; Multidrug resistance
Description: Available online 16 January 2017
Rights: © 2017 Elsevier Ltd. All rights reserved.
RMID: 0030065196
DOI: 10.1016/j.bmcl.2017.01.042
Appears in Collections:Animal and Veterinary Sciences publications

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