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J Antimicrob Chemother. 2018 Dec 1;73(12):3405-3412. doi: 10.1093/jac/dky343.

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

Author information

1
Clinic Unit of Infectious Diseases Microbiology and Preventive Medicine, Institute of Biomedicine of Seville IBiS University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
2
Institute for Research in Biomedicine (IRB Barcelona) Barcelona Institute for Science and Technology (BIST), Barcelona, Spain.
3
Barcelona Centre for International Health Research (CRESIB Hospital Clínic-Universitat de Barcelona), Barcelona, Spain.
4
Faculty of Chemistry, University of Barcelona, Barcelona, Spain.

Abstract

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.

PMID:
30188994
DOI:
10.1093/jac/dky343

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