Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 73, Issue 12, Pages 3405-3412Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dky343
Keywords
-
Funding
- Consejeria de Salud y Bienestar Social [PI12-0069]
- Consejeria de Economia, Innovacion, Ciencia y Empleo of Andalusia, Spain [CTS-6173/12]
- Instituto de Salud Carlos III, Ministerio de Economia, Industria y Competitividad [PI15/01358]
- Plan Nacional de I! D! i 2013-2016
- Instituto de Salud Carlos III, Subdireccion General de Redes y Centros de Investigacion Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0009]
- Ministerio de Economia, Industria y Competitividad [Bio2016-75327-R]
- European Development Regional Fund 'A way to achieve Europe', Operative programme Intelligent Growth 2014-2020
- Generalitat de Catalunya (XRB) [2017SGR0998, 2014LLAV-00064]
- Subprograma Miguel Servet Tipo I from the Ministerio de Economia y Competitividad of Spain [CP15/01358]
- Severo Ochoa Award of Excellence from MINECO (Government of Spain)
Ask authors/readers for more resources
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/24h) 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, andmouse 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available