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Journal of Biomolecular Structure &... Oct 2023Antimicrobial resistance poses a significant challenge to public health, especially in developing countries, due to a substantial rise in bacterial resistance. This...
Antimicrobial resistance poses a significant challenge to public health, especially in developing countries, due to a substantial rise in bacterial resistance. This situation has become so concerning that we are now at risk of losing the effectiveness of antibiotics altogether. Recent research has firmly established that bacteria engage in a process called quorum sensing (QS). QS regulates various functions, including nutrient scavenging, immune response suppression, increased virulence, biofilm formation and mobility. , an opportunistic bacterial pathogen, plays a significant role in various medical conditions such as chronic wounds, corneal infections, burn wounds and cystic fibrosis. While antibiotics are effective in killing bacteria, only a few antibiotics, particularly those from the β-lactam group, have been studied for their impact on the quorum sensing of . Given the lack of concentrated efforts in this area, we have investigated the role of β-lactam antibiotics on various potential targets of . Based on their toxicological profiles and the average binding energy obtained through molecular docking, azlocillin and moxalactam have emerged as lead antibiotics. The binding energy for the docking of azlocillin and moxalactam with LasA was determined to be -8.2 and -8.6 kcal/mol, respectively. Molecular simulation analysis has confirmed the stable interaction of both these ligands with all three target proteins (LasI, LasA and PqsR) under physiological conditions. The results of this research underscore the effectiveness of azlocillin and moxalactam. These two antibiotics may be repurposed to target the quorum sensing of .Communicated by Ramaswamy H. Sarma.
PubMed: 37904338
DOI: 10.1080/07391102.2023.2275181 -
Journal of Biomolecular Structure &... Aug 2023The β-lactamase of is known to degrade β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems. With the discovery of an...
The β-lactamase of is known to degrade β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems. With the discovery of an extended-spectrum β-lactamase in a clinical isolate of , the bacterium has become multi-drug resistant. In this study, we aim to identify new β-lactamase inhibitors by virtually screening a total of 43 phytocompounds from two Indian medicinal plants. In the molecular docking studies, pinocembrin-7--β-D-glucopyranoside (P7G) (-9.6 kcal/mol) from and ellagic acid (EA) (-9.2 kcal/mol) from had lower binding energy than moxalactam (-8.4 kcal/mol). P7G and EA formed 5 ( and ) and 4 ( and ) conventional hydrogens bonds with the active site residues. 100 ns MD simulations revealed that moxalactam and P7G (but not EA) were able to form a stable complex. The binding free energy calculations further revealed that P7G (-59.6526 kcal/mol) formed the most stable complex with β-lactamase when compared to moxalactam (-46.5669 kcal/mol) and EA (-28.4505 kcal/mol). The HOMO-LUMO and other DFT parameters support the stability and chemical reactivity of P7G at the active site of β-lactamase. P7G passed all the toxicity tests and bioavailability tests indicating that it possesses drug-likeness. Among the studied compounds, we identified P7G of as the most promising phytocompound to combat antibiotic resistance by potentially inhibiting the β-lactamase of .Communicated by Ramaswamy H. Sarma.
PubMed: 37587843
DOI: 10.1080/07391102.2023.2248272 -
Journal of Biomolecular Structure &... Nov 2023Human lactate dehydrogenase A (LDHA) is an anaerobic glycolytic enzyme involved in the inter-conversion of pyruvate to lactate. The level of LDHA in various types of...
Human lactate dehydrogenase A (LDHA) is an anaerobic glycolytic enzyme involved in the inter-conversion of pyruvate to lactate. The level of LDHA in various types of cancer cells is found to be elevated and the dependence of cancer cells on anaerobic glycolysis is viewed as the reason for this elevation. Moreover, inhibition of LDHA activity has been shown to be effective in impairing the growth of tumors, making the LDHA as a potential target for cancer therapy. In this computational study, we have performed a pharmacophore based screening of approved drugs followed by a molecular docking based screening to find a few potential LDHA inhibitors. Molecular dynamics simulations have also been performed to examine the stability of the LDHA-drug complexes as obtained from the docking study. The result of the study showed that darunavir, moxalactam and eprosartan can bind to the active site of LDHA with high affinity in comparison to two known synthetic inhibitors of LDHA. The results of the molecular dynamics simulation showed that these drugs can bind stably with the enzyme through hydrogen bond and hydrophobic interactions. Hence, it is concluded that darunavir, moxalactam and eprosartan may be considered as potential inhibitors of LDHA and can be used for cancer therapy after proper validation of their effectiveness through in vitro, in vivo and clinical trials.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Lactate Dehydrogenase 5; Molecular Docking Simulation; Drug Repositioning; Darunavir; Moxalactam; L-Lactate Dehydrogenase; Cell Line, Tumor; Neoplasms
PubMed: 36576127
DOI: 10.1080/07391102.2022.2158134 -
The Journal of Veterinary Medical... Jun 2024One of the most significant research areas in veterinary medicine is the search for carbapenem substitutes for the treatment of extended-spectrum β-lactamase...
Estimation of latamoxef (moxalactam) dosage regimens against β-lactamase-producing Enterobacterales in dogs: a pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulation.
One of the most significant research areas in veterinary medicine is the search for carbapenem substitutes for the treatment of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E). This study applied a pharmacokinetic/pharmacodynamic (PK/PD) strategy in validating optimal latamoxef (LMX) therapeutic regimens against canine ESBL-E infections. Five dogs were administered a bolus dose of 40 mg/kg LMX intravenously to measure serum drug concentrations and determine PK indices using the noncompartmental model. The highest minimum inhibitory concentration (MIC) with a probability of target attainment ≥90% was used to compute the PK/PD cutoff values for bacteriostatic (time for which the unbound drug concentration was above the MIC [fTAM] ≥40%) and bactericidal (fTAM ≥70%) effects when administered at 20, 30, 50, and 60 mg/kg, in addition to 40 mg/kg. The cumulative fraction of response (CFR) was determined using the MIC distribution of wild-type ESBL-E in companion animals. The PK/PD cutoff values can be increased by reducing the dosing interval rather than increasing the dose per time. Based on the calculated CFRs for ESBL-producing Escherichia coli and Klebsiella pneumoniae, all LMX regimens in this study and those administered at 30-60 mg/kg every 8 and 6 hr were found to be optimal (CFR ≥90%) for exerting bacteriostatic and bactericidal effects, respectively. However, the regimens of 50 and 60 mg/kg every 6 hr may merely exert bacteriostatic effects on ESBL-producing Enterobacter cloacae. Further clinical trials are required to confirm the clinical efficacy of LMX.
PubMed: 38897952
DOI: 10.1292/jvms.24-0197