Project Summary In this competitive renewal of my Senior Research Career Scientist (SRCS) award I will continue my research, service, and teaching/mentoring efforts that have been the areas of concentration during past funding periods. My research program focuses on antibiotic resistance as it is now recognized that the ability of bacterial pathogens to evade the action of antibiotics is now one of the most important threats to worldwide public health. My research program since entering the VA Medical Research service in 1987 has been to understand the molecular basis by which bacteria develop resistance to antimicrobials with the ultimate goal of advancing basic science knowledge to improving human health. As a model system, the laboratory has largely used the human sexually transmitted pathogen Neisseria gonorrhoeae since this pathogen has historically developed resistance to every antibiotic that has been brought into clinical practice and has a remarkable ability to avoid the action of multiple host defense systems. Our research focus is of importance to both the veteran/active military and civilian populations in the United States given that over 550,000 cases of gonorrhea are reported yearly with over 50% of N. gonorrhoeae isolates resistant to one or more antibiotics. Moreover, the worldwide estimate of cases approaches 100 million with reported instances of strains resistant to front-line antibiotics (azithromycin and/or ceftriaxone). A major accomplishment of my laboratory has been the finding that mechanisms of antibiotic resistance including multidrug efflux pumps, drug permeability changes due to alterations in outer membrane structure and inner membrane homeostasis can be linked to the ability of gonococci to evade mediators of host defense and survive during experimental infections. Thus, we advanced the concept that antibiotic resistance and bacterial pathogenesis are not necessarily separate entities and should be studied together. Importantly, our basic research efforts have now reached a point where translational-driven efforts can facilitate vaccine development and new antibiotic discovery. In addition to these research efforts, I have participated in and provided leadership for multiple local, national and international endeavors to combat antibiotic resistance. These efforts include extensive peer-review service for journals and study sections, membership on national and international advisory boards for agencies advancing new antibiotic development, teaching/mentoring programs through directing an NIH-funded T32 program for pre-doctoral students, developing and directing graduate level courses, and mentoring junior faculty at the Atlanta VA and Emory University School of Medicine. These extensive efforts coupled with my ongoing productive research program will be the focus of my SRCS-supported work during the next funding period.