3-Mercapto-1,2,4-triazoles and N-acylated thiosemicarbazides as metallo-β-lactamase inhibitors

Faridoon,; Hussein, Waleed M.; Vella, Peter; Islam, Nazar Ul; Ollis, David L.; Schenk, Gerhard; McGeary, Ross P.

doi:10.1016/j.bmcl.2011.10.116

Cited by 65 publications

(35 citation statements)

References 20 publications

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“…Fragment-based lead discovery (FBLD) has proven in the past several years to be a very promising method to develop new inhibitors against both serine and metallo β-lactamases, including CTX-M Class A [61,62], AmpC Class C [28,63] and IMP-1 Class B enzymes [64,65]. It has been successfully applied in both lead identification to uncover novel chemotypes for non-covalent inhibitors, and in lead optimization to probe additional binding hot spots for covalent inhibitors.…”

Section: Hts Versus Fragment-based Methods In Inhibitor Design Againsmentioning

confidence: 99%

Fragment-Based Inhibitor Discovery Against β-Lactamase

2014

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The production of β-lactamase is one of the primary resistance mechanisms used by Gram-negative bacterial pathogens to counter β-lactam antibiotics, such as penicillins, cephalosporins and carbapenems. There is an urgent need to develop novel β-lactamase inhibitors in response to ever evolving β-lactamases possessing an expanded spectrum of β-lactam hydrolyzing activity. Whereas traditional high-throughput screening has proven ineffective against serine β-lactamases, fragment-based approaches have been successfully employed to identify novel chemical matter, which in turn has revealed much about the specific molecular interactions possible in the active site of serine and metallo β-lactamases. In this review, we summarize recent progress in the field, particularly: the identification of novel inhibitor chemotypes through fragment-based screening; the use of fragment-protein structures to understand key features of binding hot spots and inform the design of improved leads; lessons learned and new prospects for β-lactamase inhibitor development using fragment-based approaches.

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Section: Hts Versus Fragment-based Methods In Inhibitor Design Againsmentioning

confidence: 99%

Fragment-Based Inhibitor Discovery Against β-Lactamase

2014

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“…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). Interestingly, the final affinity value of the lead compound was comparable to that of L-captopril for IMP-1 (11 and 12.5 M, respectively) (85) (Fig.…”

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

confidence: 97%

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

Drawz

Papp-Wallace

Bonomo

2014

Antimicrob Agents Chemother

259

179

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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.

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“…Consequently, most efforts to prepare new inhibitors towards the MBLs involve finding small molecules that bind to the active sites of the enzymes [22][23][24][25][26]. The results of the present study suggest that a different strategy to inhibit MBLs may be possible.…”

Section: Table 3 Free Energy Activation Of Intermediate Formation Andmentioning

confidence: 62%

“…Therefore, there is an urgent need to discover new clinical inhibitors of the MBLs, and these inhibitors could be co-administered with existing β-lactam-containing antibiotics. Many non-clinical inhibitors have been reported [22][23][24][25][26], and several of these compounds target the metal centre(s) in the MBLs. Mechanism-based inhibitors originating from substrate analogues may offer the best hope for new and effective MBL inhibitors [66].…”

Section: Discussionmentioning

confidence: 99%

“…The most clinically significant MBLs appear to be the NDM, IMP and VIM variants, and these enzymes have appeared in K. pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and other organisms [20,21]. A number of reversible and metal-chelating inhibitors of the MBLs have been reported; however, there are no clinically approved inhibitors [22][23][24][25][26]. A mechanism-based inhibitor was reported in 2005; however, little development of this compound as a lead has been reported in the subsequent 9 years [27].…”

Section: Introductionmentioning

confidence: 97%

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Targeting metallo-carbapenemases via modulation of electronic properties of cephalosporins

Yang

Young

et al. 2014

Biochemical Journal

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The global proliferation of metallo-carbapenemase-producing Enterobacteriaceae has created an unmet need for inhibitors of these enzymes. The rational design of metallo-carbapenemase inhibitors requires detailed knowledge of their catalytic mechanisms. Nine cephalosporins, structurally identical except for the systematic substitution of electron-donating and withdrawing groups in the para position of the styrylbenzene ring, were synthesized and utilized to probe the catalytic mechanism of New Delhi metallo-β-lactamase (NDM-1). Under steady-state conditions, K(m) values were all in the micromolar range (1.5-8.1 μM), whereas k(cat) values varied widely (17-220 s(-1)). There were large solvent deuterium isotope effects for all substrates under saturating conditions, suggesting a proton transfer is involved in the rate-limiting step. Pre-steady-state UV-visible scans demonstrated the formation of short-lived intermediates for all compounds. Hammett plots yielded reaction constants (ρ) of -0.34 ± 0.02 and -1.15 ± 0.08 for intermediate formation and breakdown, respectively. Temperature-dependence experiments yielded ΔG(‡) values that were consistent with the Hammett results. These results establish the commonality of the formation of an azanide intermediate in the NDM-1-catalysed hydrolysis of a range cephalosporins with differing electronic properties. This intermediate is a promising target for judiciously designed β-lactam antibiotics that are poor NDM-1 substrates and inhibitors with enhanced active-site residence times.

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3-Mercapto-1,2,4-triazoles and N-acylated thiosemicarbazides as metallo-β-lactamase inhibitors

Cited by 65 publications

References 20 publications

Fragment-Based Inhibitor Discovery Against β-Lactamase

Fragment-Based Inhibitor Discovery Against β-Lactamase

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

Targeting metallo-carbapenemases via modulation of electronic properties of cephalosporins

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