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.
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China.
Hui
H
Wang
Jingru
J
Meng
Min
M
Jia
Xue
X
Ma
Gonghao
G
He
Jichen
J
Yu
Rutao
R
Wang
Hui
H
Bai
Zheng
Z
Hou
Xiaoxing
X
Luo
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D003428:Cross Infection / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial; D015870:Gene Expression; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics; D008826:Microbial Sensitivity Tests; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000378:metabolism*; D010878:Piperacillin / Q000494:pharmacology*; D011094:Polyethyleneimine / Q000378:metabolism; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D004337:Drug Carriers; D008081:Liposomes; D026901:Membrane Transport Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C402263:OprM protein, Pseudomonas aeruginosa; D011094:Polyethyleneimine; D010878:Piperacillin