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Tytuł pozycji:

A small molecule that disrupts S. Typhimurium membrane voltage without cell lysis reduces bacterial colonization of mice.

Tytuł:
A small molecule that disrupts S. Typhimurium membrane voltage without cell lysis reduces bacterial colonization of mice.
Autorzy:
Dombach JL; Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, United States of America.
Quintana JL; Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, United States of America.
Allgood SC; Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, United States of America.
Nagy TA; Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, United States of America.
Gustafson DL; Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
Detweiler CS; Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, United States of America.
Źródło:
PLoS pathogens [PLoS Pathog] 2022 Jun 10; Vol. 18 (6), pp. e1010606. Date of Electronic Publication: 2022 Jun 10 (Print Publication: 2022).
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural
Język:
English
Imprint Name(s):
Original Publication: San Francisco, CA : Public Library of Science, c2005-
MeSH Terms:
Bacterial Outer Membrane Proteins*/metabolism
Gram-Negative Bacteria*/metabolism
Animals ; Anti-Bacterial Agents/metabolism ; Anti-Bacterial Agents/pharmacology ; Bacteria/metabolism ; Biological Transport ; Cell Membrane/metabolism ; Mammals ; Mice
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Grant Information:
P30 CA046934 United States CA NCI NIH HHS; R21 AI121365 United States AI NIAID NIH HHS; R21 AI151979 United States AI NIAID NIH HHS; R33 AI121365 United States AI NIAID NIH HHS
Substance Nomenclature:
0 (Anti-Bacterial Agents)
0 (Bacterial Outer Membrane Proteins)
Entry Date(s):
Date Created: 20220610 Date Completed: 20220627 Latest Revision: 20220716
Update Code:
20240105
PubMed Central ID:
PMC9223311
DOI:
10.1371/journal.ppat.1010606
PMID:
35687608
Czasopismo naukowe
As pathogenic bacteria become increasingly resistant to antibiotics, antimicrobials with mechanisms of action distinct from current clinical antibiotics are needed. Gram-negative bacteria pose a particular problem because they defend themselves against chemicals with a minimally permeable outer membrane and with efflux pumps. During infection, innate immune defense molecules increase bacterial vulnerability to chemicals by permeabilizing the outer membrane and occupying efflux pumps. Therefore, screens for compounds that reduce bacterial colonization of mammalian cells have the potential to reveal unexplored therapeutic avenues. Here we describe a new small molecule, D66, that prevents the survival of a human Gram-negative pathogen in macrophages. D66 inhibits bacterial growth under conditions wherein the bacterial outer membrane or efflux pumps are compromised, but not in standard microbiological media. The compound disrupts voltage across the bacterial inner membrane at concentrations that do not permeabilize the inner membrane or lyse cells. Selection for bacterial clones resistant to D66 activity suggested that outer membrane integrity and efflux are the two major bacterial defense mechanisms against this compound. Treatment of mammalian cells with D66 does not permeabilize the mammalian cell membrane but does cause stress, as revealed by hyperpolarization of mitochondrial membranes. Nevertheless, the compound is tolerated in mice and reduces bacterial tissue load. These data suggest that the inner membrane could be a viable target for anti-Gram-negative antimicrobials, and that disruption of bacterial membrane voltage without lysis is sufficient to enable clearance from the host.
Competing Interests: The authors have declared that no competing interests exist.
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