Dipyridyl-substituted thiosemicarbazone as a potent broad-spectrum inhibitor of metallo-β-lactamases

Li, Jiaqi; Han, Guang; Zhai, Le; Sun, Le-Yun; Chen, Cheng; Chigan, Jia-Zhu; Ding, Huan‐Huan; Yang, Ke‐Wu

doi:10.1016/j.bmc.2021.116128

Cited by 10 publications

(10 citation statements)

References 38 publications

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“…Moreover, S5 –meropenem treatment significantly reduced the bacteria loads in mice models infected with a carbapenem-resistant K. pneumonia clinical isolate. 89 This comprehensive study promotes compound S5 as a notable inhibitor of NDM-1 amenable for antibiotic development. Similarly, S6 and S7 also displayed excellent inhibitory effects against NDM-1, with IC 50 values of 1.6 and 1.69 μM and K i values of 1.59 and 1.70 μM, respectively.…”

Section: Inhibitors Of New Delhi Metallo-β-lactamasementioning

confidence: 92%

“…Cytotoxicity testing on the Vero-E6 cell line showed IC 50 values between 100 to 200 μM, indicating ideal potential for safety and low toxicity. 89 Two H2dpa derivatives containing pentadentate ligands, (R)-6,6′-(((1-carboxyethyl)azanediyl)bis(methylene))dipicolinic acid (S6) and (S)-6,6′-(((1-carboxyethyl)azanediyl) bis(methylene))dipicolinic acid (S7), potently inhibited IMP-1 with IC 50 values of 1.56 and 1.54 μM, and K i values of 1.57 and 1.54 μM, respectively. In combination, S6-meropenem and S7-meropenem were effective against multiple IMP-4producing clinical isolates.…”

Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 99%

“…Cytotoxicity testing on the Vero-E6 cell line showed IC 50 values between 100 to 200 μM, indicating ideal potential for safety and low toxicity. 89…”

Section: Inhibitors Of Imipenemase (Imp)mentioning

confidence: 99%

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Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

2023

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Section: Inhibitors Of New Delhi Metallo-β-lactamasementioning

confidence: 92%

Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 99%

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Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

2023

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“…The content of Zn(II) in the samples after dialysis was determined by ICP-MS (Li et al, 2021;Turkan et al, 2020). The IMP-1 treated by EDTA lose 1.8 equivalents of Zn(II) compared with the control group, indicating that EDTA inhibited IMP-1 by removing Zn(II) in the active site of the enzyme (Figure 6b).…”

Section: Analysis Of Hydrolysatementioning

confidence: 99%

Hydroxamates as a potent skeleton for the development of metallo‐β‐lactamase inhibitors

Chigan

Ding

et al. 2021

Chem Biol Drug Des

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Bacterial resistance caused by metallo-βlactamases (MβLs) has become an emerging public health threat, and the development of MβLs inhibitor is an effective way to overcome the resistance. In this study, thirteen novel O-aryloxycarbonyl hydroxamates were constructed and assayed against MβLs. The obtained molecules specifically inhibited imipenemase-1 (IMP-1) and New Delhi metallo-βlactamase-1, exhibiting an IC 50 value in the range of 0.10-18.42 and 0.23-22.33 μM, respectively. The hydroxamate 5 was found to be the most potent inhibitor, with an IC 50 of 0.1 and 0.23 μM using meropenem and cefazolin as substrates. ICP-MS analysis showed that 5 did not coordinate to the Zn(II) ions at the active site of IMP-1, while the rapid dilution, thermal shift and MALDI-TOF assays revealed that the hydroxamate formed a covalent bond with the enzyme. Cytotoxicity assays indicated that the hydroxamates have low toxicity in MCF-7 cells. This work provided a potent scaffold for the development of MβLs inhibitors.

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“…Dipyridyl-substituted thiosemicarbazones competitively and reversibly inhibited NDM-1. The inhibition of MBLs by thiosemicarbazones was identified to be by the Zn(II) binding ability of a sulfur group in the compound (Li et al, 2021). Octyl gallate, a FDA approved antioxidant was identified to potentiate β-lactam antibiotics, penicillin, ampicillin and cephalothin against MRSA by increasing the bacterial cell wall permeability (Tamang et al, 2022).…”

Section: Novel β-Lactam Potentiatorsmentioning

confidence: 99%

β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward

et al. 2023

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β-lactam antibiotics are one of the most widely used and diverse classes of antimicrobial agents for treating both Gram-negative and Gram-positive bacterial infections. The β-lactam antibiotics, which include penicillins, cephalosporins, monobactams and carbapenems, exert their antibacterial activity by inhibiting the bacterial cell wall synthesis and have a global positive impact in treating serious bacterial infections. Today, β-lactam antibiotics are the most frequently prescribed antimicrobial across the globe. However, due to the widespread use and misapplication of β-lactam antibiotics in fields such as human medicine and animal agriculture, resistance to this superlative drug class has emerged in the majority of clinically important bacterial pathogens. This heightened antibiotic resistance prompted researchers to explore novel strategies to restore the activity of β-lactam antibiotics, which led to the discovery of β-lactamase inhibitors (BLIs) and other β-lactam potentiators. Although there are several successful β-lactam-β-lactamase inhibitor combinations in use, the emergence of novel resistance mechanisms and variants of β-lactamases have put the quest of new β-lactam potentiators beyond precedence. This review summarizes the success stories of β-lactamase inhibitors in use, prospective β-lactam potentiators in various phases of clinical trials and the different strategies used to identify novel β-lactam potentiators. Furthermore, this review discusses the various challenges in taking these β-lactam potentiators from bench to bedside and expounds other mechanisms that could be investigated to reduce the global antimicrobial resistance (AMR) burden.

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Dipyridyl-substituted thiosemicarbazone as a potent broad-spectrum inhibitor of metallo-β-lactamases

Cited by 10 publications

References 38 publications

Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

Hydroxamates as a potent skeleton for the development of metallo‐β‐lactamase inhibitors

β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward

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