Linked Life Data

20188576

Source:http://linkedlifedata.com/resource/pubmed/id/20188576

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2010-3-10
pubmed:abstractText
The bis-indoles are a novel class of compounds with potent antibacterial activity against a broad spectrum of Gram-positive and Gram-negative pathogens. The mechanism of action of these compounds has not been clearly defined. To study the mechanism of action of bis-indoles, selections for mutants of Staphylococcus aureus NCTC 8325 with reduced susceptibility to several chemically related bis-indoles were carried out using serial passages in subinhibitory compound concentrations. Resistant mutants were only obtained for one of the four bis-indoles tested (MBX-1090), and these appeared at concentrations up to 16X MIC within 10-12 passages. MBX-1090 resistance mutations produced a truncated open reading frame of mepR (SAOUHSC_00314), a gene encoding a MarR-like repressor. MepR regulates expression of mepA (SAOUHSC_00315), which encodes a member of the Multidrug and Toxic Compound Extrusion (MATE) family of efflux pumps. MBX-1090 resistance was reverted when mepR (wild type) was provided in trans. Microarray experiments and RT-PCR experiments confirmed that over-expression of mepA is required for resistance. Interestingly, MBX-1090 resistant mutants and strains overexpressing mepA from an expression vector did not exhibit cross-resistance to closely related bis-indole compounds. MBX-1090 did not induce expression of mepA, suggesting that this compound does not directly interact with MepR. Conversely, the bis-indoles that were not substrates of MepA strongly induced mepA expression. The results of this study suggest that MepA and MepR exhibit remarkably distinct substrate specificity for closely related bis-indoles.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1464-3391
pubmed:author
pubmed:copyrightInfo
Copyright 2010 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
18
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2123-30
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Efflux-mediated bis-indole resistance in Staphylococcus aureus reveals differential substrate specificities for MepA and MepR.
pubmed:affiliation
Microbiotix, Inc., Worcester, MA 01605-4332, United States. topperman@microbiotix.com
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S.