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Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity
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نویسنده
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starkey m. ,lepine f. ,maura d. ,bandyopadhaya a. ,lesic b. ,he j. ,kitao t. ,righi v. ,milot s. ,tzika a. ,rahme l.
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منبع
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plos pathogens - 2014 - دوره : 10 - شماره : 8
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چکیده
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Etiological agents of acute,persistent,or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. pseudomonas aeruginosa is an opportunistic gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. here,we target the mvfr-regulated p. aeruginosa quorum sensing (qs) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. using a whole-cell high-throughput screen (hts) and structure-activity relationship (sar) analysis,we identify compounds that block the synthesis of both pro-persistence and pro-acute mvfr-dependent signaling molecules. these compounds,which share a benzamide-benzimidazole backbone and are unrelated to previous mvfr-regulon inhibitors,bind the global virulence qs transcriptional regulator,mvfr (pqsr); inhibit the mvfr regulon in multi-drug resistant isolates; are active against p. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. in addition,they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. as such,these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections. © 2014 starkey et al.
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آدرس
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department of surgery,harvard medical school and massachusetts general hospital,boston,ma,united states,department of microbiology and immunobiology,harvard medical school,boston,ma,united states,shriners hospitals for children boston,boston,ma,united states,american college of physicians,philadelphia,pa, United States, inrs-institut armand frappier,laval,qc, Canada, department of surgery,harvard medical school and massachusetts general hospital,boston,ma,united states,department of microbiology and immunobiology,harvard medical school,boston,ma,united states,shriners hospitals for children boston,boston,ma, United States, department of surgery,harvard medical school and massachusetts general hospital,boston,ma,united states,department of microbiology and immunobiology,harvard medical school,boston,ma,united states,shriners hospitals for children boston,boston,ma, United States, department of surgery,harvard medical school and massachusetts general hospital,boston,ma,united states,department of microbiology and immunobiology,harvard medical school,boston,ma,united states,shriners hospitals for children boston,boston,ma, United States, department of surgery,harvard medical school and massachusetts general hospital,boston,ma,united states,department of microbiology and immunobiology,harvard medical school,boston,ma,united states,shriners hospitals for children boston,boston,ma, United States, department of surgery,harvard medical school and massachusetts general hospital,boston,ma,united states,department of microbiology and immunobiology,harvard medical school,boston,ma,united states,shriners hospitals for children boston,boston,ma, United States, nmr surgical laboratory,department of surgery,massachusetts general and shriners hospitals,harvard medical school,boston,ma,united states,athinoula a. martinos center of biomedical imaging,department of radiology,massachusetts general hospital,boston,ma, United States, inrs-institut armand frappier,laval,qc, Canada, nmr surgical laboratory,department of surgery,massachusetts general and shriners hospitals,harvard medical school,boston,ma,united states,athinoula a. martinos center of biomedical imaging,department of radiology,massachusetts general hospital,boston,ma, United States, department of surgery,harvard medical school and massachusetts general hospital,boston,ma,united states,department of microbiology and immunobiology,harvard medical school,boston,ma,united states,shriners hospitals for children boston,boston,ma, United States
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Authors
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