Grant: Project Grant

According to the United Nations (UN) and the World Health Organization (WHO) antimicrobial resistance (AMR) is one the largest threats to public health and economic growth. Recently, the WHO for the first time divided pathogens into three categories according to the urgency of need for new antibiotics: critical, high and medium priority. The most critical group of all includes multidrug resistant bacteria that pose a particular threat in hospitals, nursing homes, and among patients whose care requires devices such as ventilators and blood catheters. They include Acinetobacter, Pseudomonas and various Enterobacteriaceae that cause severe and often deadly infections such as bloodstream infections and pneumonia. Despite significant investments by industry and academia into antibiotic discovery and development over the past decades, no new antibiotic class with novel mode(s) of action to fight these pathogens has been approved in half a century. The reasons for this failure have been identified and are caused by the inability of current compounds to penetrate into bacteria (low permeability) and their likelihood of being pumped out (efflux). To overcome this bottleneck in antibacterial drug discovery, we plan to develop helper molecules (adjuvants) designed to enhance membrane permeability, reduce efflux of antibiotics and prevent or delay resistance development against these pathogens. The overall goal of this proposal is to identify optimized helper molecules capable of rescuing antibiotics from resistance in animal models of infection against multidrug-resistant priority pathogens and to understand their mode of actions.