Pyrrolomycins Are Potent Natural Protonophores
Type de document :
Compte-rendu et recension critique d'ouvrage
DOI :
PMID :
Titre :
Pyrrolomycins Are Potent Natural Protonophores
Auteur(s) :
Valderrama, Katherine [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Pradel, Elizabeth [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Lille Inflammation Research International Center - U 995 [LIRIC]
Firsov, Alexander [Auteur]
Lomonosov Moscow State University [MSU]
Drobecq, Hervé [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Bauderlique-Le Roy, Hélène [Auteur]
Institut Pasteur de Lille
Villemagne, Baptiste [Auteur]
Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 [M2SV]
Antonenko, Yuri [Auteur]
Lomonosov Moscow State University [MSU]
Hartkoorn, Ruben Christiaan [Auteur correspondant]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Pradel, Elizabeth [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Lille Inflammation Research International Center - U 995 [LIRIC]
Firsov, Alexander [Auteur]
Lomonosov Moscow State University [MSU]
Drobecq, Hervé [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Bauderlique-Le Roy, Hélène [Auteur]
Institut Pasteur de Lille
Villemagne, Baptiste [Auteur]
Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 [M2SV]
Antonenko, Yuri [Auteur]
Lomonosov Moscow State University [MSU]
Hartkoorn, Ruben Christiaan [Auteur correspondant]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Titre de la revue :
Antimicrobial Agents and Chemotherapy
Pagination :
e01450-19
Éditeur :
American Society for Microbiology
Date de publication :
2019-09-23
ISSN :
0066-4804
Mot(s)-clé(s) en anglais :
antibiotic
antibiotic resistance
mechanisms of action
protonophore
pyrrolomycin
uncoupler
antibiotic resistance
mechanisms of action
protonophore
pyrrolomycin
uncoupler
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
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 ...
Lire la suite >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, yet with an 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 medium plays a large role in pyrrolomycin activity. The selection of resistant mutants allowed for the characterization and validation of a number of mechanisms of resistance to pyrrolomycins in both Staphylococcus aureus and an Escherichia coli ΔtolC mutant, all of which appear to affect compound penetration rather than being target associated. Imaging of the impact of pyrrolomycin on the E. coli ΔtolC mutant using scanning electron microscopy showed blebbing of the bacterial cell wall often at the site of bacterial division. Using potentiometric probes and an electrophysiological technique with an artificial bilayer lipid membrane, it was demonstrated that pyrrolomycins C and D are very potent membrane-depolarizing agents, an order of magnitude more active than conventional carbonyl cyanide m-chlorophenylhydrazone (CCCP), specifically disturbing the proton gradient and uncoupling oxidative phosphorylation via protonophoric action. This work clearly unveils the until-now-elusive mechanism of action of pyrrolomycins and explains their antibiotic activity as well as mechanisms of innate and acquired drug resistance in bacteria.Lire moins >
Lire la suite >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, yet with an 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 medium plays a large role in pyrrolomycin activity. The selection of resistant mutants allowed for the characterization and validation of a number of mechanisms of resistance to pyrrolomycins in both Staphylococcus aureus and an Escherichia coli ΔtolC mutant, all of which appear to affect compound penetration rather than being target associated. Imaging of the impact of pyrrolomycin on the E. coli ΔtolC mutant using scanning electron microscopy showed blebbing of the bacterial cell wall often at the site of bacterial division. Using potentiometric probes and an electrophysiological technique with an artificial bilayer lipid membrane, it was demonstrated that pyrrolomycins C and D are very potent membrane-depolarizing agents, an order of magnitude more active than conventional carbonyl cyanide m-chlorophenylhydrazone (CCCP), specifically disturbing the proton gradient and uncoupling oxidative phosphorylation via protonophoric action. This work clearly unveils the until-now-elusive mechanism of action of pyrrolomycins and explains their antibiotic activity as well as mechanisms of innate and acquired drug resistance in bacteria.Lire moins >
Langue :
Anglais
Vulgarisation :
Non
Source :
Fichiers
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761498/pdf
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