Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors.
Metallo-β-lactamases (MBLs) represent one of the most important and widespread mechanisms of resistance to β-lactam antibiotics (including the life-saving carbapenems), against which no clinically useful inhibitors are currently available. We report herein a structure-based high-throughput docking (HTD) campaign on three clinically-relevant acquired MBLs (IMP-1, NDM-1 and VIM-2). The initial hit NF1810 (1) was optimized providing the broad-spectrum inhibitor 3i, which is able to potentiate the in vitro activity of cefoxitin on a VIM-2-producing E. coli strain.
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , Siena , Italy.|b Department of Biotechnology , Chemistry and Pharmacy, University of Siena , Siena , Italy.
Margherita
M
Brindisi
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , Siena , Italy.|b Department of Biotechnology , Chemistry and Pharmacy, University of Siena , Siena , Italy.
Simone
S
Brogi
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , Siena , Italy.|b Department of Biotechnology , Chemistry and Pharmacy, University of Siena , Siena , Italy.
Simone
S
Giovani
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , Siena , Italy.|b Department of Biotechnology , Chemistry and Pharmacy, University of Siena , Siena , Italy.
Sandra
S
Gemma
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , Siena , Italy.|b Department of Biotechnology , Chemistry and Pharmacy, University of Siena , Siena , Italy.
Stefania
S
Lamponi
c Department of Medical Biotechnology , University of Siena , Siena , Italy , and.
Filomena
F
De Luca
d Department of Pharmacy , University of Napoli Federico II , Napoli , Italy.
Ettore
E
Novellino
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , Siena , Italy.|b Department of Biotechnology , Chemistry and Pharmacy, University of Siena , Siena , Italy.
Giuseppe
G
Campiani
c Department of Medical Biotechnology , University of Siena , Siena , Italy , and.
Jean-Denis
JD
Docquier
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena , Siena , Italy.|b Department of Biotechnology , Chemistry and Pharmacy, University of Siena , Siena , Italy.
Stefania
S
Butini
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
Antibiotic resistance; docking; metallo-β-lactamase