Structure-based virtual screening for the discovery of novel inhibitors of New Delhi Metallo-β-lactamase-1

Bacterial resistance has become a worldwide concern after the emergence of metallo β-lactamases MBLs. They represent one of the major mechanisms of bacterial resistance against beta-lactam antibiotics. Among MBLs, New Delhi metallo-β-lactamase-1 NDM-1, the most prevalent type, is extremely efficient in inactivating nearly all-available antibiotics including last resort carbapenems. No inhibitors for NDM-1 are currently available in therapy, making the spread of NDM-1 producing bacterial strains a serious menace. In this perspective, we performed a structure-based in silico screening of a commercially available library using FLAPdock and identified several, non β-lactam derivatives as promising candidates active against NDM-1. The binding affinities of the highest scoring hits were measured in vitro revealing, for some of them, low micromolar affinity towards NDM-1. For the best inhibitors, efficacy against resistant bacterial strains overexpressing NDM-1 was validated, confirming their favorable synergistic effect in combination with the carbapenem MeropenemBacterial resistance has become a worldwide concern after the emergence of metallo-β-lactamases (MBLs). They represent one of the major mechanisms of bacterial resistance against beta-lactam antibiotics. Among MBLs, New Delhi metallo-β-lactamase-1 NDM-1, the most prevalent type, is extremely efficient in inactivating nearly all-available antibiotics including last resort carbapenems. No inhibitors for NDM-1 are currently available in therapy, making the spread of NDM-1 producing bacterial strains a serious menace. With this perspective, we performed a structure-based in silico screening of a commercially available library using FLAPdock and identified several, non-β-lactam derivatives as promising candidates active against NDM-1. The binding affinities of the highest scoring hits were measured in vitro revealing, for some of them, low micromolar affinity toward NDM-1. For the best inhibitors, efficacy against resistant bacterial strains overexpressing NDM-1 was validated, confirming their favorable synergistic effect in combination with the carbapenem Meropenem