Journal
CHEMMEDCHEM
Volume 13, Issue 7, Pages 713-724Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201700788
Keywords
bacterial resistance; boron; cell viability; inhibitors; X-ray diffraction
Categories
Funding
- Instituto de Salud Carlos III
- Subdireccion General de Redes y Centros de Investigacion Cooperativa
- Ministerio de Economia y Competitividad
- Spanish Network for Research in Infectious Diseases (REIPI) - European Development Regional Fund A way to achieve Europe ERDF [RD12/0015]
- FAR (Finanziamento di Ateneo per la Ricerca) from University of Modena
- Reggio Emilia
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The emergence and dissemination of multidrug resistant (MDR) pathogens resistant to nearly 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 the KPC-2 active site by small phenylboronic acid derivatives. Four new phenylboronic acid derivatives were designed and tested against KPC-2. For the most active, despite their simple chemical structures, nanomolar affinity was achieved. The new derivatives restored susceptibility to meropenem in clinical strains overexpressing KPC-2. Moreover, no cytotoxicity was detected in cell-viability assays, which further validated the designed leads. Two crystallographic binary complexes of the best inhibitors binding KPC-2 were obtained at high resolution. Kinetic descriptions of slow binding, time-dependent inhibition, and interaction geometries in KPC-2 were fully investigated. This study will ultimately lead toward the optimization and development of more-effective KPC-2 inhibitors.
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