Pyrrolomycins are Potent Natural Protonophoresстатья

Статья опубликована в высокорейтинговом журнале

Информация о цитировании статьи получена из Scopus, Web of Science
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 24 сентября 2020 г.

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[1] Pyrrolomycins are potent natural protonophores / K. Valderrama, E. Pradel, A. M. Firsov et al. // Antimicrobial Agents and Chemotherapy. — 2019. — Vol. 63, no. 10. — P. e01450–19. The escalating burden of antibiotic drug resistance necessitates research into novel classes of antibiotics and their mechanism of action. Pyrrolomycins are a family of potent natural product antibiotics with nanomolar activity against Gram-positive bacteria, with a yet elusive mechanism of action. In this work, we dissect the apparent Gram-positive specific activity of pyrrolomycins and show that Gram-negative bacteria are equally sensitive to pyrrolomycins when drug efflux transporters are removed, and that albumin in media plays a large role in pyrrolomycin activity. Selection of resistant mutants allowed for the characterisation and validation of a number of mechanisms of resistance to pyrrolomycins in both S. aureus and E. coli ΔtolC, all of which appear to affect compound penetration, rather than being target associated. Imaging of the impact of pyrrolomycin on E. coli ΔtolC using scanning electron microscopy, showed blebbing of the bacterial cell wall often at the site of bacterial division. Using potentiometric probes and electrophysiological technique with artificial bilayer lipid membrane it was demonstrated that pyrrolomycins C and D are very potent membrane depolarising agents, an order of magnitude more active than conventional CCCP, specifically disturbing the proton gradient and uncoupling oxidative phosphorylation via protonophoric action. This work clearly unveils the till now elusive mechanism of action of pyrrolomycins and explains their antibiotic activity as well as mechanisms of innate and acquired drug resistance in bacteria. [ DOI ]

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