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Antimicrob. Agents Chemother. doi:10.1128/AAC.00670-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Targeting Type III Secretion in Yersinia pestis

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655 USA

^* To whom correspondence should be addressed. Email: jon.goguen{at}umassmed.edu.

	Abstract

Yersinia pestis, the causative agent of plague, utilizes a plasmid-encoded type III secretion system (T3SS) to aid resistance to host defenses. This system injects a set of effector proteins known as Yops (Yersinia outer proteins) into the cytosol of host cells that come into contact with the bacteria. The T3SS is absolutely required for Y. pestis virulence, making it a potential target for new therapeutics. Using a novel and simple high throughput screening method, we examined a diverse collection of chemical libraries for small molecules that inhibit type III secretion in Y. pestis. Primary screening of 70,966 compounds and mixtures yielded 421 presumptive inhibitors. We selected eight of these for further analysis in secondary assays. Four of the eight compounds effectively inhibited Yop secretion at micro molar concentrations. Interestingly, we observed differential inhibition among Yop species with some compounds. The compounds did not inhibit bacterial growth at the concentrations used in the inhibition assays. Three compounds protected HeLa cells from type III secretion-dependent cytotoxicity. Of the eight compounds examined in secondary assays, four show good promise as leads for structure-activity relationship studies. They are a diverse group, each having a chemical scaffold not only distinct from each other, but also distinct from previous described candidate type III secretion inhibitors.