-Lactamase-mediated bacterial resistance continues to evolve toward a broader substrate spectrum, including the most potent -lactam antibiotics, the carbapenems. New carbapenemases include both serine hydrolases, such as the class A KPC -lactamases, as well as the class B metallo--lactamases (MBLs), such as NDM-1, which has spread globally since its appearance just five years ago. This project will prepare and evaluate atypically substituted bicyclic -lactams, including both carbapenems and penams, to assess the potential to further develop these -lactam scaffolds as poor substrates and/or inhibitors of the MBLs. The project is guided by recent structural data on acyl-enzymes of key penicillin-binding proteins (PBPs), particularly including PBP3 from Pseudomonas aeruginosa and Acinetobacter baumannii, as well as complexes of hydrolyzed antibiotics with the MBLs, particularly including complexes of NDM-1. The positions to be modified represent positions that have not been extensively examined, due to synthetic difficulty. Several collaborators including, Peter Oeschlaeger, Robert Bonomo, German Bou, and Natalie Strynadka will provide kinetic, microbiological, and structural information, respectively, on the interactions of the newly synthesized antibiotics and the MBLs.
This project will utilize recently reported structural data to guide the synthesis of new -lactam antibiotics which are less susceptible to metallo--lactamases, enzymes which can hydrolyze nearly all current -lactam antibiotics. The strategy involves appending substituents at key positions, representing positions that have not been thoroughly examined. New synthetic chemistry has already been developed to facilitate this investigation.