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The resistance of Pseudomonas aeruginosa to antibiotics is multi factorial and complex. Whereas efflux pumps such as MexAB-OprM have been thought to predominate, here we show that a novel ATP Binding Cassette (ABC) transporter that mediates influx of carbenicillin from the periplasm to the cytoplasm and away from its cell wall target plays an important role in the resistance of P. aeruginosa to this antibiotic. Treatment of P. aeruginosa with verapamil, an inhibitor of ABC transporters in eukaryotic cells, increases its sensitivity to carbenicillin. Using amino acid sequence homology with known verapamil protein targets as a probe, we determined that the PA1113 gene product, an ABC transporter, mediates carbenicillin uptake into the bacterial cytoplasm. Docking and pharmacological analyses showed that verapamil and carbenicillin compete for the same site on the PA1113 gene protein, explaining the inhibitory effect of verapamil on carbenicillin uptake, and furthermore suggest that the PA1113 ABC transporter accounts for about 30% of P. aeruginosa carbenicillin resistance. Our findings demonstrate that the PA1113 gene product helps mediate carbenicillin resistance by transporting it away from its cell wall target and represents a promising new therapeutic target.

Identification of the PA1113 Gene Product as an ABC Transporter Involved in the Uptake of Carbenicillin in Pseudomonas aeruginosa PAO1