PA3225 is a transcriptional repressor of antibiotic resistance mechanisms in Pseudomonas aeruginosa [PublishAheadOfPrint]

The tssABC1 locus is part of the Hcp secretion island (HSI) -I type VI secretion system (T6SS) in Pseudomonas aeruginosa. Previous work has implicated the tssC1 gene in P. aeruginosa biofilm-specific antibiotic resistance, and tssC1 is preferentially expressed in biofilms compared to planktonic cells. Using a DNA-dependent protein pulldown approach, we discovered PA3225, an uncharacterised LysR-type transcriptional regulator that specifically bound to the tssABC1 upstream regulatory region. Deletion of PA3225 led to a two-fold decrease in tssA1 expression in planktonic cells compared to wild-type, and tssA1 expression was slightly reduced in PA3225 biofilms compared to wild-type biofilms. Intriguingly, further investigations revealed that the PA3225 mutant was less susceptible to multiple, structurally unrelated antibiotics with various mechanisms of action when growing planktonically. The PA3225 mutant was additionally more resistant to ciprofloxacin when growing in a biofilm. The decreased antibiotic susceptibility of the PA3225 strain was linked to transcriptional upregulation of the MexAB-OprM efflux pump. Using RNA-seq, other PA3225-regulated genes were identified, and the products of these genes, such as the putative ABC transporter PA3228, may also contribute to antibiotic resistance.

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