Keeping drug-resistant infection at bay for safer extended space travel

During extended space travel, while the virulence and drug resistance of pathogenic microbes escalate, the defense of the immune system of the crew plummets. The risk of infectious outbreaks increases with the duration of the mission and presents a realistic concern that may hamper the success of NASA missions in space exploration. The focus of this study is to address the drug resistance issue of bacterial infections. Specifically, we will investigate the mechanism of multi-drug efflux transporters in Gram-negative bacterial pathogens, which are the major cellular player conferring both intrinsic and acquired multi-drug resistance (MDR) to these organisms. A thorough understanding of the molecular mechanism of these transporters is critical for the identification of novel target site to enable the rational design of inhibitors. Effective transporter inhibitors, when used in combination with antimicrobials, will greatly increase the efficacy of treatment. Toward this goal, we will determine the correlation between the stability and activity of Escherichia coli MDR transporter AcrB, which will provide guidelines and benchmark parameters for the design of inhibitors that target the biogenesis process of AcrB and related transporters. In addition, we will conduct mutational studies to identify key residues that are critical for the function of AcrB, as well as residues that may restore the function of functionless mutants. Analyses of how mutations at different sites affect the function of the protein will cast new insights into our understanding about how these transporters function and therefore, how to interrupt with their operations.