The emergence and dissemination of multi drug resistant (MDR) pathogens resistant to near all available antibiotics poses a significant threat in clinical therapy. Among them, Klebsiella pneumoniae clinical isolates overexpressing KPC-2 carbapenemase are the most worrisome, extending bacterial resistance to last resort carbapenems. In this study we investigate the molecular recognition requirements in KPC-2 active site by small phenyl boronic acid derivatives. Four new phenyl boronic acid derivatives were designed and tested vs KPC-2. For the most active, despite their simple chemical structures, nanomolar affinity was achieved. New derivatives restored susceptibility to meropenem in clinical strains overexpressing KPC-2. Moreover no cytotoxicity was detected in cell viability assays, further validating the designed leads. Two crystallographic binary complexes of best inhibitors binding KPC-2 were obtained at high resolution. Kinetic descriptions of slow binding, time dependent inhibition and interactions geometries in KPC-2 were fully investigated. This study will ultimately lead toward optimization and development of more effective KPC-2 inhibitors.
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