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Synergistic interaction between phenothiazines and antimicrobial agents against Burkholderia pseudomallei

Ying Ying Chan1, Yong Mei Ong, Kim Lee Chua

  • 1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore.

Antimicrobial Agents and Chemotherapy
|December 6, 2006
PubMed

Insights

Phenothiazine drugs like prochlorperazine enhance antibiotic effectiveness against Burkholderia pseudomallei, the cause of melioidosis. These drugs reduce antibiotic resistance by inhibiting efflux pumps, lowering minimum inhibitory concentrations and protecting cells from infection.

Area of Science:

  • Microbiology
  • Pharmacology

Background:

  • Melioidosis is a severe septicemic disease caused by Burkholderia pseudomallei, endemic in Southeast Asia and Australia.
  • Intrinsic antibiotic resistance in B. pseudomallei is largely due to drug efflux pumps.
  • Inhibiting these efflux pumps can restore antibiotic efficacy against resistant bacteria.

Purpose of the Study:

  • To investigate the synergistic effects of phenothiazine drugs with antimicrobial agents against B. pseudomallei.
  • To explore the mechanism by which phenothiazines enhance antimicrobial activity.

Main Methods:

  • Minimum Inhibitory Concentration (MIC) assays were performed for various antimicrobial agents alone and in combination with phenothiazines.
  • Drug accumulation studies were conducted using fluorescently labeled erythromycin.
  • Cell protection assays were used to evaluate the efficacy of combined treatments against B. pseudomallei infection in human lung epithelial and macrophage cells.

Main Results:

  • Phenothiazines (prochlorperazine, chlorpromazine, promazine) showed synergistic activity with several antibiotics, including streptomycin, erythromycin, and levofloxacin, reducing their MICs up to 8,000-fold.
  • Omeprazole, a proton pump inhibitor, mimicked the synergistic effect, suggesting involvement of the proton gradient.
  • Phenothiazines increased intracellular accumulation of erythromycin in B. pseudomallei cells.
  • Low concentrations of erythromycin combined with phenothiazines protected host cells from B. pseudomallei infection and reduced cytotoxicity.

Conclusions:

  • Phenothiazines act as efflux pump inhibitors, restoring the potency of various antibiotics against B. pseudomallei.
  • The mechanism likely involves disruption of the proton motive force across the bacterial membrane.
  • Combined phenothiazine-antibiotic therapy holds promise for treating melioidosis and overcoming antibiotic resistance.

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