UMMS Affiliation

Department of Molecular Genetics and Microbiology

Date

11-19-2008

Document Type

Article

Subjects

Anti-Bacterial Agents; Antibodies, Bacterial; Bacterial Outer Membrane Proteins; Bacterial Translocation; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Escherichia coli; Hela Cells; Humans; Plasmids; Yersinia pestis

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Yersinia pestis, the causative agent of plague, utilizes a plasmid-encoded type III secretion system (T3SS) to aid it with its 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. T3SS is absolutely required for the virulence of Y. pestis, 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. The 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 micromolar 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, with each having a chemical scaffold not only distinct from each other but also distinct from previously described candidate type III secretion inhibitors.

Rights and Permissions

Citation: Antimicrob Agents Chemother. 2009 Feb;53(2):385-92. Epub 2008 Nov 17. Link to article on publisher's site

DOI of Published Version

10.1128/AAC.00670-08

Related Resources

Link to Article in PubMed

Journal Title

Antimicrobial agents and chemotherapy

PubMed ID

19015348

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.