Project SummaryThe beginning of the 21st century has seen the evolution and dissemination of highly resistant Gram-negativepathogens, especially including carbapenem resistant Enterobacteriaceae (CRE), including Klebsiellapneumoniae and Escherichia coli, as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Thisproject entails the development of new antibiotics, in the form of carbapenems, to counteract these resistantmicroorganisms. The carbapenems are modified in specific ways to improve penetration of the Gram-negative bacterial outer membrane, to elude 21st century carbapenemases, and to improve binding to theirspecific targets, the penicillin binding proteins. Strong initial data supports the hypothesis that we cansuccessfully modify key properties, such as carbapenemase stability and permeation of Gram-negativepathogens through appropriate structural changes. It is also desired to render the new antibiotics morespecific for their selected pathogen. This concept is also supported by strong initial data, demonstrating thata highly atypical modification of the carbapenem scaffold can improve activity against Mycobacteriumtuberculosis. We propose to design molecules to specifically target the L,D-transpeptidase of Mycobacteriumtuberculosis, to enable the generation of a carbapenem which can selectively eradicate this pathogen withoutadversely affecting commensal microbiota.Numerous collaborations are in place with leading academic and commercial scientists to assessantibacterial potency, carbapenemase resilience, target transpeptidase binding, transport, and cytotoxicity.Initial results of these assays are promising, with several newly designed carbapenems displaying propertiessuperior to meropenem, the best current commercial carbapenem antibiotic.