Induction of multiple antibiotic resistance in Bacteroides fragilis by benzene and benzene-derived active compounds of commonly used analgesics, antiseptics and cleaning agents.
OBJECTIVE
To determine the potential of active compounds (ACs) present in commonly used analgesics/antiseptics and cleaning agents (detergents and disinfectants) to induce multiple antibiotic resistance (MAR) in Bacteroides fragilis.


METHODS
B. fragilis ATCC 25285 untreated or pretreated with sublethal concentrations of ACs (n = 25) was grown for 12 h. Susceptibility of cells pre-treated with various ACs to antibiotics and expression of resistance nodulation division family (bmeB) efflux pumps and putative marA-like global activators (PGAs) were measured.


RESULTS
Twelve aromatic ACs containing benzene or its activated derivatives (salicylate, acetaminophen, gingerol, benzoate, phenol, chlorhexidine gluconate, capsaicin, juglone, cinnamaldehyde, benzene, ibuprofen and Triton X-100) induced MAR, which was reduced by carbonyl cyanide m-chlorophenylhydrazone. There was a positive correlation between the predicted degree of benzene activation and the level of induction. Deactivated benzene or non-aromatic ACs were either poor inducers or non-inducers. Efflux pumps bmeB1, 3, 4, 7 and two PGAs bfrA1 and bfrA2 were overexpressed. Expression of bfrA1 or bfrA2 in Escherichia coli caused a >2-fold increase in the MAR and overexpression of acrB, suggesting that they were putative marA orthologues.


CONCLUSIONS
These data demonstrate (i) the presence of an MarA-like system(s) in B. fragilis and (ii) the propensity of benzene or its activated derivatives present in pharmaceutical products to induce MAR.
Pumbwe
Lilian
L
Greater Los Angeles Veterans Administration Healthcare Systems, University of California, Los Angeles, CA 90073, USA. lilskil@ucla.edu
Skilbeck
Christopher A
CA
Wexler
Hannah M
HM
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001441:Bacteroides fragilis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D001554:Benzene / Q000737:chemistry / Q000494:pharmacology*; D003902:Detergents / Q000737:chemistry / Q000494:pharmacology*; D004202:Disinfectants / Q000737:chemistry / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008969:Molecular Sequence Data
D000700:Analgesics; D000891:Anti-Infective Agents, Local; D001426:Bacterial Proteins; D003902:Detergents; D004202:Disinfectants; D001554:Benzene