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- Title
Synergistic activity of an OmpA inhibitor and colistin against colistin-resistant Acinetobacter baumannii: mechanistic analysis and in vivo efficacy.
- Authors
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
- Abstract
<bold>Objectives: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
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
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2018, Vol 73, Issue 12, p3405
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dky343