Journal of Antimicrobial Chemotherapy 2018; 73(12): 3405 - 3412

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

Parra-Millán R, Vila-Farrés X, Ayerbe-Algaba R, Varese M, Sánchez-Encinales V, Bayó N, Pachón-Ibáñez ME, Teixidó M, Vila J, Pachón J, Giralt E, Smani Y
01.12.2018

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\xE2\x80\x89mg/kg/24\xE2\x80\x89h) in combination with a sub-optimal dose of colistin (10\xE2\x80\x89mg/kg/24\xE2\x80\x89h) 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.