The discovery and development of new chemotherapeutic agents for hospital acquired infections

Omonike Olaleye olaleyeoa@tsu.edu

Abstract

Background: Enterococcus faecalis (E. faecalis) is a major cause of hospital acquired infections (HAI). About 721,800 HAI occur in the United States in 2011 (Magill SS, et. al). E. faecalis infections are difficult to treat and the emergence of drug resistant strains have reduced the efficacy of current chemotherapeutic options. Therefore, novel ways to treat patients infected with E. faecalis infections are needed. Methionine aminopeptidase (MetAP), a metalloprotease that catalyzes the removal of the initiating N-terminal methionine from proteins and polypeptides is a promising and attractive antibacterial drug target. N-terminal methionine excision is an essential process required for post-translational modifications for a large number of proteins. Our hypothesis is that therapeutically targeting N-terminal processing of essential E. faecalis proteins will treat and/or limit the progression and dissemination of this pathogen in patients.
Methods: To evaluate the therapeutic potential of MetAP in E. faecalis, we cloned, overexpressed and purified the only MetAP in E. faecalis: EfMetAP1. The recombinant enzyme was characterized to determine optimal kinetic conditions required for activity. To identify inhibitors of this enzyme in vitro, we used a target-based approach and screened a library of over 175,000 structurally diverse small molecules against EfMetAP1 at the Johns Hopkins University School of Medicine. Following this analysis, we determined the potency of these inhibitors on E. faecalis and other clinically relevant pathogens in collaboration with colleagues at Johns Hopkins University School of Public Health.
Results: We discovered a new class of potent inhibitors of EfMetAP1. We found that this pharmacophore showed potent activity against E. faecalis strains with minimum inhibitory concentrations in the low micro molar range. Based on these findings, we assert that EfMetAP1 is a promising and novel antibacterial drug target for potential treatment of infections caused by E. faecalis.
Conclusion: The clinical significance of this study is that the therapeutic targeting of EfMetAP1 activity in E. faecalis related infections, would accelerate the future development of new agents to treat drug-resistant nosocomial infections in the clinic.
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