Grant: Operating Grant

Our most safe and effective antibiotics are the Beta-lactams; however, the protection they offer against infection is being eroded by the increasing prevalence of bacterial pathogens expressing AmpC beta-lactamase. AmpC is found in many bacteria including Pseudomonas aeruginosa, a significant opportunistic pathogen of humans that is associated with considerable morbidity and mortality in intensive care units (ICU) and cystic fibrosis patients. Capable of hyper-producing AmpC in response to beta-lactam exposure, P. aeruginosa rapidly develops clinical resistance to most available beta-lactams; thus, there is a need to better understand how P. aeruginosa regulates ampC gene expression in response to beta-lactams, and to develop alternative approaches to surmount ampC mediated antibiotic resistance. Production of AmpC depends on the activity of three proteins: AmpR, NagZ and AmpG. Exposure to beta-lactams prompts these proteins to turn on AmpC production to destroy the antibiotic and promote bacterial survival. Because AmpC itself is highly resistant to clinically available inhibitors, we are examining the structural and functional biology of NagZ, AmpR and AmpG and using this information to guide the development small molecules that block their function. We hypothesize that blocking the function of these proteins with small molecules will increase the efficacy of beta-lactams against bacteria that harbor ampC.