Effect of the solvent in the four systems NDM-1 and L209F and direct measure of the extent backbone overall fluctuation in complexed and uncomplexed system.

<p>Effect of the solvent in the four systems NDM-1 and L209F and direct measure of the extent backbone overall fluctuation in complexed and uncomplexed system.</p

Sequence alignment of NDM-1 with the sequence of some B1 MBLs.

<p>In the top is shown the secondary structure annotation of NDM-1 (PDB-ID 3Q6X). Arrows indicates β-strands, TTT and TT strict α and β-turn respectively; spirals indicate α-helices. Red letters indicate similar residue; red background indicate the identical residues, and blue boxes indicate conserved position. Aligned sequence was made using EsPrit (v.3.0).</p

Antimicrobial susceptibility test.

<p>Antimicrobial susceptibility test.</p

Network of contacts among L209 (a) and F209 (b) and neighbor residues.

<p>(a) percentage of occurrence of short-distance contacts in the case of free NDM-1 (black numbers) and complexed NDM-1 (red numbers). (b) percentage of occurrence of short-distance contacts in the case of free L209F (black numbers) and complexed L209F (red numbers).</p

Kinetic parameters of NDM-1 and L209F enzymes.

<p>Kinetic parameters of NDM-1 and L209F enzymes.</p

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