Aminoacyl β-naphthylamides as substrates and modulators of AcrB multidrug efflux pump

Proceedings of the National Academy of Sciences of the United States of America
Alfred D KinanaH Nikaido

Abstract

Efflux pumps of the resistance-nodulation division superfamily, such as AcrB, make a major contribution to multidrug resistance in Gram-negative bacteria. Inhibitors of such pumps would improve the efficacy of antibiotics, and ameliorate the crisis in health care caused by the prevalence of multidrug resistant Gram-negative pathogens. Phenylalanyl-arginine β-naphthylamide (PAβN), is a well-known inhibitor of AcrB and its homologs. However, its mechanism of inhibition is not clear. Because the hydrolysis of PAβN in Escherichia coli was nearly entirely dependent on an aminopeptidase, PepN, expression of PepN in periplasm allowed us to carry out a quantitative determination of PAβN efflux kinetics through the determination of its periplasmic concentrations by quantitation of the first hydrolysis product, phenylalanine, after a short period of treatment. We found that PAβN is efficiently pumped out by AcrB, with a sigmoidal kinetics. We also examined the behavior of PAβN homologs, Ala β-naphthylamide, Arg β-naphthylamide, and Phe β-naphthylamide, as substrates of AcrB and as modulators of nitrocefin efflux through AcrB. Furthermore, molecular dynamics simulations indicated that the mode of binding of these compounds to AcrB affects...Continue Reading

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Citations

Jun 16, 2016·Future Medicinal Chemistry·Fernando CoronaJosé L Martínez
Oct 27, 2016·Biochemical Pharmacology·Çiğdem Yılmaz, Gülay Özcengiz
Mar 16, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gabriella SpenglerLeonard Amaral
Sep 11, 2018·Expert Opinion on Drug Discovery·Paula BlancoManuel Alcalde-Rico
Mar 5, 2017·Essays in Biochemistry·Venkata Krishnan RamaswamyPaolo Ruggerone
Jul 16, 2020·MBio·Robert L MarshallLaura J V Piddock
May 4, 2017·Medicina·Valeryia MikalayevaRimantas Daugelavičius
Feb 23, 2017·Nature Microbiology·Muriel MasiJean-Marie Pagès
Feb 1, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sabine SchusterWinfried V Kern
Feb 6, 2020·International Journal of Molecular Sciences·Alessio AtzoriPaolo Ruggerone
Feb 5, 2021·Accounts of Chemical Research·Helen I ZgurskayaValentin V Rybenkov
Feb 8, 2020·Biochimica Et Biophysica Acta. General Subjects·Adam T GreenHelen I Zgurskaya
May 4, 2021·Current Opinion in Microbiology·Helen I ZgurskayaPaolo Ruggerone
May 10, 2019·The Journal of Physical Chemistry. B·Alessio AtzoriPaolo Ruggerone

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