This Article Full Text Full Text (PDF) Other Versions of this Article: AAC.01033-06v1 51/2/623    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chan, Y. Y. Articles by Chua, K. L. Search for Related Content PubMed PubMed Citation Articles by Chan, Y. Y. Articles by Chua, K. L.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2007, p. 623-630, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01033-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Synergistic Interaction between Phenothiazines and Antimicrobial Agents against Burkholderia pseudomallei

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore

Received 17 August 2006/ Returned for modification 23 October 2006/ Accepted 17 November 2006

The gram-negative soil bacillus Burkholderia pseudomallei is the causative agent of melioidosis, a severe and potentially fatal septicemic disease that is endemic to Southeast Asia and northern Australia. Its intrinsic resistance to many antibiotics is attributed mainly to the presence of several drug efflux pumps, and therefore, inhibitors of such pumps are expected to restore the activities of many clinically important antimicrobial agents that are the substrates of these pumps. The phenothiazine antipsychotic and antihistaminic drugs prochlorperazine, chlorpromazine, and promazine have a synergistic interaction with a wide spectrum of antimicrobial agents, thereby enhancing their antimicrobial potency against B. pseudomallei. Antimicrobial agents that interacted synergistically with the phenothiazines include streptomycin, erythromycin, oleandomycin, spectinomycin, levofloxacin, azithromycin, and amoxicillin-clavulanic acid. The MICs of these antibiotics were reduced as much as 8,000-fold in the presence of the phenothiazines. Antimicrobial agents which did not interact synergistically with the phenothiazines include gentamicin, amoxicillin, and ampicillin. Omeprazole, a proton pump inhibitor, provided an augmentation of antimicrobial activities similar to that of the phenothiazines, suggesting that the phenothiazines might have interfered with the proton gradient at the inner membrane. B. pseudomallei cells accumulated more erythromycin in the presence of the phenothiazines, an effect similar to that of carbonyl cyanide m-chlorophenylhydrazone, a proton gradient uncoupler. In the presence of the phenothiazines, a much reduced concentration of erythromycin (0.06x MIC) also protected human lung epithelial cells and macrophage cells from B. pseudomallei infection and attenuated its cytotoxicity.

Published ahead of print on 4 December 2006.

This article has been cited by other articles:

• Bailey, A. M., Paulsen, I. T., Piddock, L. J. V. (2008). RamA Confers Multidrug Resistance in Salmonella enterica via Increased Expression of acrB, Which Is Inhibited by Chlorpromazine. Antimicrob. Agents Chemother. 52: 3604-3611 [Abstract] [Full Text]