NDM-1 and its variants are the most prevalent types of metallo-β-lactamases, hydrolyze almost all antibiotics of β-lactam group leading to multiple-drug resistance in bacteria. No inhibitor has yet been obtained for NDM-1 or other class of metallo-β-lactamases. Therefore, strategies to identify novel anti-β-lactamase agents with specific mechanisms of action are the need of an hour. In this study, we have reported the discovery of novel non-β-lactam inhibitors against NDM-1 by multi-step virtual screening approach. The potential for virtually screened drugs was estimated through in vitro cell assays. Five chemical compounds were finally purchased and evaluated experimentally for their efficacies to inhibit NDM-1 producing bacterial cells, in vitro. The dissociation constants (Kd), association constant (Ka), stoichiometry (n) and binding energies (ΔG) of compounds with the respective targets were determined using isothermal titration calorimetry (ITC). Molecular dynamic simulation carried out for 25 ns revealed that these complexes were stable throughout the simulation with relative RMSD in acceptable range. Moreover, Microbiological and kinetic studies further confirmed high efficacies of these inhibitors by reducing the minimum inhibitory concentration (MIC) and catalysis of antibiotics by β-lactamases in the presence of inhibitors. Therefore, we conclude that these potential inhibitors may be used as lead molecules for future drug candidates.
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http://dx.doi.org/10.1038/s41598-017-09588-1 | DOI Listing |
In Vitro Cell Dev Biol Anim
January 2025
Department of Outpatient Service, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, China.
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View Article and Find Full Text PDFBreast Cancer Res Treat
January 2025
Department of Breast Surgery, Thyroid Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, No.141, Tianjin Road, Huangshi, 435000, Hubei, China.
Background: The heterogeneity of breast cancer (BC) necessitates the identification of novel subtypes and prognostic models to enhance patient stratification and treatment strategies. This study aims to identify novel BC subtypes based on PANoptosis-related genes (PRGs) and construct a robust prognostic model to guide individualized treatment strategies.
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Eur J Drug Metab Pharmacokinet
January 2025
Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
Caffeine consumption is regarded as a widespread phenomenon, and its usage has continued to increase. In addition, the growing usage of antidepressants worldwide and increase in mental health disorders were shown in recent statistical analyses conducted by the World Health Organisation. The coadministration of caffeine and antidepressants remains a concern due to potential interactions that can alter a patient's response to therapy.
View Article and Find Full Text PDFNeurosurg Rev
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Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Ticagrelor has become the standard drug for the treatment of intracranial aneurysms (IAs) with flow diverters (FDs), but the dosage has not been standardized. The effect of platelet function on clinical and imaging prognosis remains unclear. This study aimed to show the effects of different doses of ticagrelor and platelet aggregation function on the clinical and imaging prognosis after FDs treatment of aneurysms.
View Article and Find Full Text PDFActa Pharmacol Sin
January 2025
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
Patients suffering epilepsy caused by the gain-of-function mutants of the hKCNT1 potassium channels are drug refractory. In this study, we cloned a novel human KCNT1B channel isoform using the brain cDNA library and conducted patch-clamp and molecular docking analyses to characterize the pharmacological properties of the hKCNT1B channel using thirteen drugs. Among cinchona alkaloids, we found that hydroquinine exerted the strongest blocking effect on the hKCNT1B channel, especially the F313L mutant.
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