Abstract:
: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.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Celenza G,Vicario M,Bellio P,Linciano P,Perilli M,Oliver A,Blazquez J,Cendron L,Tondi Ddoi
10.1002/cmdc.201700788subject
Has Abstractpub_date
2018-04-06 00:00:00pages
713-724issue
7eissn
1860-7179issn
1860-7187journal_volume
13pub_type
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