The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening

Vella, Peter; Hussein, Waleed M.; Leung, Eleanor; Clayton, Daniel; Ollis, David L.; Mitić, Nataša; Schenk, Gerhard; McGeary, Ross P.

doi:10.1016/j.bmcl.2011.04.027

Cited by 70 publications

(58 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To illustrate, a modified form of fragment screening was employed to identify lead molecules for inhibition of the increasingly common IMP-1 enzyme, followed by in silico studies of the binding mechanisms of 1,2,4-triazole-3-thiols (85,86). While optimization of the initial thiols yielded compounds with only mid-M affinities, derivatives of thiosemicarbazides achieved low-M affinity (range of 11 to 75 M) (87).…”

Section: The Unique Challenge Of Class B Mbls; Closer Than We Think?mentioning

confidence: 99%

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Drawz

Papp-Wallace

Bonomo

2014

Antimicrob Agents Chemother

257

176

View full text Add to dashboard Cite

As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing ␤-lactamase enzymes to this serious clinical problem. This review highlights recent advances in ␤-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the ␤-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new ␤-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner ␤-lactam and dosing regimens for these promising agents. This "renaissance" of ␤-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

show abstract

Section: The Unique Challenge Of Class B Mbls; Closer Than We Think?mentioning

confidence: 99%

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Drawz

Papp-Wallace

Bonomo

2014

Antimicrob Agents Chemother

257

176

View full text Add to dashboard Cite

show abstract

“…The NDM-1 Q119D mutant showed lower levels of catalytic efficiency toward ampicillin, meropenem, ertapenem, and cefepime substrates tested in the enzyme kinetic assay than seen with NDM-1 (19). Further, residue 119 has been reported to be involved in binding of inhibitors in IMP-1, BlaB, and CphA (5,7,20,21), biapenem in CphA (22) and penicillin substrates in NDM-1 (23,24). The effect of substitutions of E119 in TMB-1 was studied here.…”

mentioning

confidence: 93%

“…The dissemination of carbapenemases is a major public health problem, and there has been no effective MBL inhibitor available to date that could restore the effect of ␤-lactams when coadministered. Fragment-based library screening has shown that fragments containing a thiol group are able to inhibit MBLs (5). Thiol fragments are thought to inhibit MBLs through bridging the two zinc ions in the active site, by replacing the bridging hydroxyl ion (6).…”

mentioning

confidence: 99%

Structural Insights into TMB-1 and the Role of Residues 119 and 228 in Substrate and Inhibitor Binding

Skagseth

Christopeit

Akhter

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Metallo-␤-lactamases (MBLs) threaten the effectiveness of ␤-lactam antibiotics, including carbapenems, and are a concern for global public health. ␤-Lactam/␤-lactamase inhibitor combinations active against class A and class D carbapenemases are used, but no clinically useful MBL inhibitor is currently available. Tripoli metallo-␤-lactamase-1 (TMB-1) and TMB-2 are members of MBL subclass B1a, where TMB-2 is an S228P variant of TMB-1. The role of S228P was studied by comparisons of TMB-1 and TMB-2, and E119 was investigated through the construction of site-directed mutants of TMB-1, E119Q, E119S, and E119A (E119Q/S/A). All TMB variants were characterized through enzyme kinetic studies. Thermostability and crystallization analyses of TMB-1 were performed. Thiol-based inhibitors were investigated by determining the 50% inhibitory concentrations (IC 50 ) and binding using surface plasmon resonance (SPR) for analysis of TMB-1. Thermostability measurements found TMB-1 to be stabilized by high NaCl concentrations. Steady-state enzyme kinetics analyses found substitutions of E119, in particular, substitutions associated with the penicillins, to affect hydrolysis to some extent. TMB-2 with S228P showed slightly reduced catalytic efficiency compared to TMB-1. The IC 50 levels of the new thiol-based inhibitors were 0.66 M (inhibitor 2a) and 0.62 M (inhibitor 2b), and the equilibrium dissociation constant (K D ) of inhibitor 2a was 1.6 M; thus, both were more potent inhibitors than L-captopril (IC 50 ϭ 47 M; K D ϭ 25 M). The crystal structure of TMB-1 was resolved to 1.75 Å. Modeling of inhibitor 2b in the TMB-1 active site suggested that the presence of the W64 residue results in T-shaped -stacking and R224 cation-interactions with the phenyl ring of the inhibitor. In sum, the results suggest that residues 119 and 228 affect the catalytic efficiency of TMB-1 and that inhibitors 2a and 2b are more potent inhibitors for TMB-1 than L-captopril.

show abstract

“…Os mecanismos de resistência aos -lactâmicos mais comumente descritos nesses agentes são alteração da membrana externa, produção de -lactamase, efluxo e alteração no sítio de ação dos -lactâmicos (Kohler et al, 1999;Okamoto et al, 2001;Okamoto et al, 2002, Vella et al, 2011.…”

Section: Mecanismos De Resistênciaunclassified

Detecção fenotípica e genotípica de carbapenemases em isolados de hemoculturas de Pseudomonas aeruginosa e Acinetobacter spp

Fung¹

View full text Add to dashboard Cite

The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening

Cited by 70 publications

References 31 publications

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Structural Insights into TMB-1 and the Role of Residues 119 and 228 in Substrate and Inhibitor Binding

Detecção fenotípica e genotípica de carbapenemases em isolados de hemoculturas de Pseudomonas aeruginosa e Acinetobacter spp

Contact Info

Product

Resources

About