Affiliation:
1. Antimicrobial Agents Research Group, Department of Immunity and Infection, The Medical School, The University of Birmingham, Birmingham B15 2TT, United Kingdom
2. The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, Maryland 20850
Abstract
ABSTRACT
Salmonella enterica
serovar Typhimurium SL1344, in which efflux pump genes (
acrB
,
acrD
,
acrF
,
tolC
) or regulatory genes thereof (
marA
,
soxS
,
ramA
) were inactivated, was grown in the presence of 240 antimicrobial and nonantimicrobial agents in the Biolog Phenotype MicroArray. Mutants lacking
tolC
,
acrB
, and
ramA
grew significantly worse than other mutants in the presence of 48 agents (some of which have not previously been identified as substrates of AcrAB-TolC) and particularly poorly in the presence of phenothiazines, which are human antipsychotics. MIC testing revealed that the phenothiazine chlorpromazine had antimicrobial activity and synergized with common antibiotics against different
Salmonella
serovars and SL1344. Chlorpromazine increased the intracellular accumulation of ethidium bromide, which was ablated in mutants lacking
acrB
, suggesting an interaction with AcrB. High-level but not low-level overexpression of
ramA
increased the expression of
acrB
; conferred resistance to chloramphenicol, tetracycline, nalidixic acid, and triclosan and organic solvent tolerance; and increased the amount of ethidium bromide accumulated. Chlorpromazine induced the modest overproduction of
ramA
but repressed
acrB
. These data suggest that phenothiazines are not efflux pump inhibitors but influence gene expression, including that of
acrB
, which confers the synergy with antimicrobials observed.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
119 articles.
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