Antimicrobial resistance: From problem to policy to action

Abstract

Background:The past decade has been a lean period for the discovery of antibiotics with very few approvals of new antibacterial agents by FDA. However, emergence of Multi Drug Resistant organisms (MDRO) and Extensively Drug Resistant organisms (XDRO) pathogens have led to increased attention to this field. Center for Disease Control and Prevention (CDC) has declared infections caused by MDR ESKAPE pathogens as a critical area of unmet medical need. Further, FDA has also announced various incentives to support the Infectious Diseases Society of America (IDSA) aspiration to develop 10 new antibiotics by 2020. In this presentation, I will discuss challenges in the discovery of antibacterial compounds with a case study of Leucine tRNA synthetase inhibitor (LRSI).Methods & Materials: Various properties of antibacterial standard of care agents analyzed with respect to physicochemical, safety and activity against MDROs/XDROs. Also, merits and demerits of novel targets vs. novel approaches were considered. In order to explore novel targets we have designed, synthesized & profiled novel LRSI. The profile of our compound was compared with reported LRSI to identify the differentials.Results: Unlike general drugs, antibacterial compounds need distinct physicochemical properties in order to work efficiently in different cellular milieu of host & pathogen. Safety (selectivity & toxicity) is critical as doses required to control the infection are usually high. New compounds should not only be effective against MDROs but also possess lower risk of resistance development and relapse. We have identified novel selective Leucine tRNA synthetase inhibitor (LRSI) for Gram negative MDROs. On analysis this compound shows distinct advantages over previously reported inhibitor.Conclusion: To circumvent the challenges in the discovery of antibacterial compounds, the Pharma industry recognizes the need of novel targets and approaches to tackle the ever evolving pathogens. Towards this pursuit we identified a novel Leucine tRNA synthetase inhibitor (LRSI) with potent activity against MDROs. Promising profile of this novel inhibitor merits further development for clinical use.