Response of Staphylococcus aureus to Salicylate Challenge

Abstract

Growth of Staphylococcus aureus with the nonsteroidal anti-inflammatory salicylate reduces susceptibility of the organism to multiple antimicrobials. Transcriptome analysis revealed that growth of S. aureus with salicylate leads to the induction of genes involved with gluconate and formate metabolism and represses genes required for gluconeogenesis and glycolysis. In addition, salicylate induction upregulates two antibiotic target genes and downregulates a multidrug efflux pump gene repressor (mgrA) and sarR, which represses a gene (sarA) important for intrinsic antimicrobial resistance. We hypothesize that these salicylate-induced alterations jointly represent a unique mechanism that allows S. aureus to resist antimicrobial stress and toxicity.In 1985, Judah L. Rosner reported on a "nonheritable" antibiotic resistance mechanism that could be induced in Escherichia coli by the nonsteroidal anti-inflammatory salicylate or aspirin (acetylsalicylate) (47). It was later reported that nonsteroidal anti-inflammatories induce expression of the E. coli multiple antibiotic resistance operon (marRAB) and that repression of marRAB by the winged-helix DNA-binding repressor MarR is alleviated upon exposure to salicylate (1,6,31). Since these initial discoveries, the ability of salicylate to induce antimicrobial resistance in multiple bacterial species has been reported (for a review, see reference 44).Growth of the gram-positive pathogen Staphylococcus aureus with salicylate also induces reduced susceptibility to multiple antimicrobials, including membrane-active cleaners/disinfectants and plant essential oils, the DNA topoisomerase inhibitor ciprofloxacin, the protein synthesis inhibitor fusidic acid, and the DNA-intercalating dye ethidium (14,15,42,43,45,46). The salicylate-induced phenotype is partially due to the activation of antimicrobial efflux and a proton motive forceindependent reduction in antimicrobial accumulation (43). The drugs for which salicylate reduces accumulation are substrates of the well-characterized multidrug efflux pump NorA, yet NorA does not play a role in this mechanism (23, 43). In addition, salicylate also increases the frequency at which S. aureus acquires genotypic resistance to ciprofloxacin and fusidic acid (14, 45).The S. aureus genome also contains numerous marR paralogs, historically referred to as the staphylococcal accessory regulator (sarA) family of genes (for a review, see reference 29). Some of these S. aureus marR paralogues (e.g., sarA, mgrA, and mepR) have already been implicated in the control of intrinsic antimicrobial resistance (21,22,36,51,52,53).We now characterize transcriptome alterations that occur in S. aureus cells exposed to salicylate and support some of these findings with physiological experimentation. The implications of our findings with respect to the salicylate-inducible multiple antimicrobial resistance mechanism of S. aureus are discussed. MATERIALS AND METHODSBacterial strains, culture conditions, growth curves, and antibiotic susceptibility determination...

Salicylic Acid DiminishesStaphylococcus aureusCapsular Polysaccharide Type 5 Expression

“…Expression of the cap operon and CP expression in S. aureus are known to be under multiple levels of control and affected by several environmental stimuli (49). Previous studies have shown that the global regulators agr, mgrA, arlRS, B , sarA, and saeRS control CP production at the transcriptional level (30,31,34,55,59).…”

The Isolation ofStaphylococcus aureusTea Tree Oil-Reduced Susceptibility Mutants

“…Household disinfectant reduced susceptibility S. aureus mutants demonstrated altered cell wall metabolism (Lamichhane-Khadka et al ., 2008) and a TTORS phenotype (Davis et al ., 2005). S. aureus grown in the presence of salicylate which activates an intrinsic multiple antimicrobial mechanism (Riordan et al ., 2007) also demonstrated TTORS (Gustafson et al ., 2001). …”

Effects of mesalamine (5-aminosalicylic acid) on bacterial gene expression

“…While 5-ASA has not previously been the subject of genomic screens in bacteria, several studies have used microarray analysis to examine the effects of salicylic acid on expression in E. coli, 25 Staphylococcus aureus, 54 and Mycobacterium tuberculosis. 55 In E. coli, for example, salicylate has been shown to regulate transcription of the multiple antibiotic resistance operon marRAB, 24 with marR encoding a negative regulator of the operon and marA encoding a transcriptional activator.…”