Antibiotic resistance has become a global alarm comparable to that of climate changes. The World Health Organization listed Acinetobacter baumannii as one of the microorganism of critical concern for its resistance to carbapenems. The oxacillinase OXA-23 represents the dominant ß-lactamase enzyme to confer resistance to carbapenems among A. baumannii clinical isolates worldwide. It was shown recently that OXA-23 interacts with several protein partners located within the outer membrane and the periplasm. Based on the hypothesis that periplasm interactors might be required to support OXA-23 enzymatic activity upon carbapenem exposure, we aimed this project at identifying periplasmic proteins that are upregulated upon addition of carbapenems in the growth medium using a proteomic approach; moreover, we will study the involvement of upregulated proteins in OXA-mediated carbapenem-resistance, fitness and virulence in A. baumannii strain AB5075.
The development of resistance to antibiotics is increasing rapidly in A. baumannii due to the intensive selective pressure provided by the large amount of antibiotics used in community and nosocomial settings. Currently, the combined administration of polymyxins and tigecycline is the only remaining treatment option (http://ecdc.europa.eu). However, several clinical isolates have been shown to be resistant to colistin (polymyxin E), leaving no more therapeutic options especially for those patients in Intensive Care Units in most need of care (Cikman et al., 2015). New drugs to combat this problem are in great demand, and therefore the study of new antibiotic molecules is definitely crucial; nevertheless, it is clear from past experiences that resistance to new drugs is often short to be developed. An alternative strategy that could potentially alleviate the current paucity of new antibiotic molecules by extending the life of current antibiotics is the study of new and selected enzymatic inhibitors. It is important to underline that the OXA-23 enzyme is the dominant oxacillinase OXA-23 among A. baumannii clinical isolates worldwide (Olaitan et al., 2013; Merino et al., 2014), and therefore it was selected for this study. We believe that the high throughput proteomics approach that will be used in this project not only helps to understand the enzymatic mechanism(s) of OXA-23 in A. baumannii but also to identify target(s) for the development of new carbapenemase inhibitors.
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