Abstract
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.
Highlights
Increasing bacterial resistance to antibiotics represents a worldwide health threat [1]
Resistance is believed to involve four separate mechanisms acting independently or in concert: (i) mutations in the genes encoding for antibiotic targets render them insensitive to drug action; (ii) changes in plasma membrane permeases and/or antibiotic trapping in the cell wall or surrounding biofilm which impede bacterial entry [2]; (iii) new genetic information acquired via plasmids or transposons encodes for inactivating enzymes such as β-lactamases [3,4]; and (iv) efflux pumps that expel antibiotics before they reach their targets
Verapamilis isused usedininclinical clinicaltherapy therapy as as an an inhibitor inhibitor of of of cardiovascular diseases such as angina pectoris, hypertension, and cardiac arrhythmias. It is cardiovascular diseases such as angina pectoris, hypertension, and cardiac arrhythmias [34]. It is used in anti-cancer therapies as an inhibitor of the main efflux pump that removes drugs used in anti-cancer therapies as an inhibitor of the main efflux pump that removes drugs from from cancer cells, membrane
Summary
Increasing bacterial resistance to antibiotics represents a worldwide health threat [1]. The most important of these are comprised of ATP-binding cassette (ABC) transporters that mediate the influx of metabolites as well as efflux of drugs and toxins [6,7]. SMR (small multidrug resistance), a subfamily of DMT (drug metabolite transporters superfamily) and MATE (multi-antimicrobial extrusion), a subfamily of MOP (oligosaccharidyl multidrug-lipid polysaccharides flippases) can be found in some species. The two families of efflux pumps most represented in bacteria, the MFS (major facilitator) and RND (resistance nodulation division) super-families, are driven by transmembrane
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