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Role of the AcrAB-TolC efflux pump in determining susceptibility of Haemophilus influenzae to the novel peptide deformylase inhibitor LBM415.

Dean, Charles and Narayan, Shubha and Daigle, Denis and Dzink-Fox, Joann and Puyang, Xiaoling and Bracken, Kathryn and Dean, Karl and Weidmann, Beat and Yuan, Zhengyu and Jain, Rakesh and Ryder, Neil (2005) Role of the AcrAB-TolC efflux pump in determining susceptibility of Haemophilus influenzae to the novel peptide deformylase inhibitor LBM415. Antimicrobial Agents and Chemotherapy, 49 (8). pp. 3129-3135. ISSN 0066-4804

Abstract

Haemophilus influenzae isolates vary widely in their susceptibilities to the peptide deformylase inhibitor LBM415 (MIC range, 0.06 to 32 microg/ml); however, on average, they are less susceptible than gram-positive organisms, such as Staphylococcus aureus and Streptococcus pneumoniae. Insertional inactivation of the H. influenzae acrB or tolC gene in strain NB65044 (Rd strain KW20) increased susceptibility to LBM415, confirming a role for the AcrAB-TolC pump in determining resistance. Consistent with this, sequencing of a PCR fragment generated with primers flanking the acrRA region from an LBM415-hypersusceptible H. influenzae clinical isolate revealed a genetic deletion of acrA. Inactivation of acrB or tolC in several clinical isolates with atypically reduced susceptibility to LBM415 (MIC of 16 microg/ml or greater) significantly increased susceptibility, confirming that the pump is also a determinant of decreased susceptibility in these clinical isolates. Examination of acrR, encoding the putative repressor of pump gene expression, from several of these strains revealed mutations introducing frameshifts, stop codons, and amino acid changes relative to the published sequence, suggesting that loss of pump repression leads to decreased susceptibility. Supporting this, NB65044 acrR mutants selected by exposure to LBM415 at 8 microg/ml had susceptibilities to LBM415 and other pump substrates comparable to the least sensitive clinical isolates and showed increased expression of pump genes.

Item Type: Article
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Additional Information: free final full text version available on publisher's official URL and on PubMedCentral; PDF self-archving not allowed except on personal websites and websites hosted by universities
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Date Deposited: 14 Dec 2009 14:07
Last Modified: 14 Dec 2009 14:07
URI: https://oak.novartis.com/id/eprint/30

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