1 research outputs found
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. With this perspective, we performed
a structure-based <i>in silico</i> 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 <i>in vitro</i> 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