title: Evaluation of a series of 2-napthamide derivatives as inhibitors of the drug efflux pump AcrB for the reversal of antimicrobial resistance.
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.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.
authors.forename: Yinhu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, SA 5000, Australia.
authors.forename: Rumana
authors.initials: R
authors.lastname: Mowla
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Guo
authors.affiliation: Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, SA 5371, Australia.
authors.forename: Abiodun D
authors.initials: AD
authors.lastname: Ogunniyi
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
authors.forename: Taufiq
authors.initials: T
authors.lastname: Rahman
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, SA 5000, Australia.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: De Barros Lopes
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address: mashutao@sdu.edu.cn.
authors.forename: Shutao
authors.initials: S
authors.lastname: Ma
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, SA 5000, Australia. Electronic address: rietie.venter@unisa.edu.au.
authors.forename: Henrietta
authors.initials: H
authors.lastname: Venter
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D002701:Chloramphenicol / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004917:Erythromycin / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009284:Naphthols / Q000737:chemistry; D017434:Protein Structure, Tertiary
chemical_list: D000577:Amides; D000890:Anti-Infective Agents; D002701:Chloramphenicol; D004917:Erythromycin; D029968:Escherichia coli Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009284:Naphthols; C083496:AcrB protein, E coli
keywords: 2-Naphthamide; AcrB; Antimicrobial resistance; Drug efflux pump; Efflux pump inhibitor; Multidrug resistance