6 research outputs found
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
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