oprM as a new target for reversion of multidrug resistance in Pseudomonas aeruginosa by antisense phosphorothioate oligodeoxynucleotides

Multidrug‐resistant Pseudomonas aeruginosa (MDR‐PA) is one of the leading Gram‐negative organisms associated with nosocomial infections. The increasing frequency of MDR‐PA has represented a huge challenge in conventional antibacterial therapy. The loss of effectiveness of commonly used antibiotics calls for the immediate need to develop an alternative strategy for combating MDR‐PA infections. The multiantibiotic resistance of MDR‐PA is largely attributable to the production of multidrug efflux pumps, MexAB‐OprM. OprM forms the antibiotic‐ejecting duct and plays a crucial role in exporting incoming chemotherapeutic agents across the membranes. Disruption of the OprM expression may inhibit the function of multidrug efflux pumps and lead to restoration of MDR‐PA susceptibility to antibiotics. In this study, we developed a novel anion liposome for encapsulating and delivering specific anti‐ oprM phosphorothioate oligodeoxynucleotide (PS‐ODN617) and polycation polyethylenimine (PEI) complexes. The additions of the encapsulated anti‐ oprM PS‐ODN617/PEI to MDR‐PA isolates caused a significant reduction of oprM expression and inhibition of MDR‐PA growth in the presence of piperacillin in a concentration‐dependent manner. The encapsulated PS‐ODN617 treatment also reduced minimal inhibitory concentrations of five most commonly used antibiotics to the sensitive margin values on MDR‐PA clinical isolates, respectively. The results of present study firstly indicate that PS‐ODN targeted to oprM can significantly restore the susceptibility of MDR‐PA to existing antibiotics, which appears to be a novel strategy for treating MDR‐PA infections.