OAK-based cochleates as a novel approach to overcome multidrug resistance in bacteria
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Antibiotic resistance has become a worldwide medical problem. To find new ways of overcoming this phenomenon, we investigated the role of the membrane-active oligo-acyl-lysyl (OAK) sequence C(12)K-7α(8), in combination with essentially ineffective antibiotics. Determination of minimal inhibitory concentration (MIC) against gram-negative multidrug-resistant strains of Escherichia coli revealed combinations with sub-MIC OAK levels that acted synergistically with several antibiotics, thus lowering their MICs by several orders of magnitude. To shed light into the molecular basis for this synergism, we used both mutant strains and biochemical assays. Our results suggest that bacterial sensitization to antibiotics was derived mainly from the OAK's capacity to overcome the efflux-enhanced resistance mechanism, by promoting backdoor entry of otherwise excluded antibiotics. To facilitate simultaneous delivery of the pooled drugs to an infection site, we developed a novel OAK-based cochleate system with demonstrable stability in whole blood. To assess the potential therapeutic use of such cochleates, we performed preliminary experiments that imitate systemic treatment of neutropenic mice infected with lethal inoculums of multidrug resistance E. coli. Single-dose administration of erythromycin coencapsulated in OAK-based cochleates has decreased drug toxicity and increased therapeutic efficacy in a dose-dependent manner. Collectively, our findings suggest a potentially useful approach for fighting efflux-enhanced resistance mechanisms.
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