Synergistic activity of an OmpA inhibitor and colistin against colistin-resistant Acinetobacter baumannii: mechanistic analysis and in vivo efficacy.

Autor:	Parra-Millán, Raquel, Ayerbe-Algaba, Rafael, Sánchez-Encinales, Viviana, Pachón-Ibáñez, María Eugenia, Pachón, Jerónimo, Smani, Younes, Vila-Farrés, Xavier, Varese, Monica, Bayó, Nuría, Teixidó, Meritxell, Giralt, Ernest, Vila, Jordi
Předmět:	OMPA protein COLISTIN DRUG resistance in bacteria ACINETOBACTER baumannii BACTERIAL disease prevention ACINETOBACTER infections ANIMAL experimentation ANTIBIOTICS BIOLOGICAL models COMPARATIVE studies DRUG synergism ENZYME inhibitors MASS spectrometry RESEARCH methodology MEDICAL cooperation MEMBRANE proteins MICE MICROBIAL sensitivity tests RESEARCH EVALUATION research TREATMENT effectiveness GRAM-negative aerobic bacteria CHEMICAL inhibitors PHARMACODYNAMICS
Zdroj:	Journal of Antimicrobial Chemotherapy (JAC); Dec2018, Vol. 73 Issue 12, p3405-3412, 8p
Abstrakt:	Objectives: Preventing bacterial contact with host cells can provide an additional approach to tackling MDR Acinetobacter baumannii. Recently, we identified AOA-2 as a potential blocker of A. baumannii outer membrane protein A without presenting bactericidal activity. Here, we aimed to study whether AOA-2 can increase the activity of colistin against colistin-resistant A. baumannii in vitro and in vivo.Methods: Reference and clinical A. baumannii strains susceptible and resistant to colistin (CST-S and CST-R) were used. Microdilution and time-kill curve assays were performed to determine the synergy between AOA-2 and colistin. SDS-PAGE assays with CST-S and CST-R outer membrane proteins and MALDI-TOF-TOF (MS-MS/MS) analysis were performed to determine the AOA-2 and colistin synergy mechanism. In a murine peritoneal sepsis model, the therapeutic efficacy of AOA-2 (10 mg/kg/24 h) in combination with a sub-optimal dose of colistin (10 mg/kg/24 h) against CST-R was evaluated by determining the bacterial load in tissues and blood, and mouse survival.Results: We showed that AOA-2 increased the in vitro colistin susceptibility of reference and clinical CST-S and CST-R strains. This combination also enhanced their killing activity after 24 h of drug exposure. This synergy is mediated by the overexpression of Omp25. In vivo, the combination of AOA-2 with colistin significantly reduced the bacterial load in tissues and blood, and increased mouse survival, compared with colistin monotherapy.Conclusions: We identified a novel class of antimicrobial agents that has proven to be effective in combination with colistin in an experimental model of severe infection by CST-R A. baumannii. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
Externí odkaz:	Zobrazit plný text záznamu