Pan-genome mediated therapeutic target mining in Kingella kingae and inhibition assessment using traditional Chinese medicinal compounds: an informatics approach.

Kingella kingae causes bacteremia, endocarditis, osteomyelitis, septic arthritis, meningitis, spondylodiscitis, and lower respiratory tract infections in pediatric patients. Usually it demonstrates disease after inflammation of mouth, lips or infections of the upper respiratory tract. To date, therapeutic targets in this bacterium remain unexplored. We have utilized a battery of bioinformatics tools to mine these targets in this study. Core genes were initially inferred from 55 genomes of K. kingae and 39 therapeutic targets were mined using an in-house pipeline. We selected aroG product (KDPG aldolase) involved in chorismate pathway, for inhibition analysis of this bacterium using lead-like metabolites from traditional Chinese medicinal plants. Pharmacophore generation was done using control ZINC36444158 (1,16-bis[(dihydroxyphosphinyl)oxy]hexadecane), followed by molecular docking of top hits from a library of 36,000 compounds. Top prioritized compounds were ZINC95914016, ZINC33833283 and ZINC95914219. ADME profiling and simulation of compound dosing (100 mg tablet) was done to infer compartmental pharmacokinetics in a population of 300 individuals in fasting state. PkCSM based toxicity analysis revealed the compounds ZINC95914016 and ZINC95914219 as safe and with almost similar bioavailability. However, ZINC95914016 takes less time to reach maximum concentration in the plasma and shows several optimal parameters compared to other leads. In light of obtained data, we recommend this compound for further testing and induction in experimental drug design pipeline.Communicated by Ramaswamy H. Sarma.

Development and Evaluation of Novel Encapsulated Isoeugenol-Liposomal Gel Carrier System for Methicillin-Resistant Staphylococcus aureus.

In recent years, methicillin-resistant Staphylococcus aureus (MRSA) bacteria have seriously threatened the health and safety of the world's population. This challenge demands the development of alternative therapies based on plant origin. This molecular docking study ascertained the orientation and intermolecular interactions of isoeugenol within penicillin-binding protein 2a. In this present work, isoeugenol as an anti-MRSA therapy was selected by encapsulating it into a liposomal carrier system. After encapsulation into the liposomal carrier, it was evaluated for encapsulation efficiency (%), particle size, zeta potential, and morphology. The percentage entrapment efficiency (% EE) was observed to be 57.8 ± 2.89% with a particle size of 143.31 ± 7.165 nm, a zeta potential of (-)25 mV, and morphology was found to be spherical and smooth. After this evaluation, it was incorporated into a 0.5% Carbopol gel for a smooth and uniform distribution on the skin. Notably, the isoeugenol-liposomal gel was smooth on the surface with a pH of 6.4, suitable viscosity, and spreadability. Interestingly, the developed isoeugenol-liposomal gel was safe for human use, with more than 80% cell viability. The in vitro drug release study shows promising results with 75.95 ± 3.79% of drug release after 24 h. The minimum inhibitory concentration (MIC) was 8.236 µg/mL. Based on this, it can be concluded that encapsulating isoeugenol into the liposomal gel is a potential carrier for MRSA treatment.

Pan-Genomics of Escherichia albertii for Antibiotic Resistance Profiling in Different Genome Fractions and Natural Product Mediated Intervention: In Silico Approach.

Escherichia albertii is an emerging, enteric pathogen of significance. It was first isolated in 2003 from a pediatric diarrheal sample from Bangladesh. In this study, a comprehensive in silico strategy was followed to first list out antibiotic-resistant genes from core, accessory and unique genome fractions of 95 available genomes of E. albertii. Then, 56 drug targets were identified from the core essential genome. Finally, ZipA, an essential cell division protein that stabilizes the FtsZ protofilaments by cross-linking them and serves as a cytoplasmic membrane anchor for the Z ring, was selected for further downstream processing. It was computationally modeled using a threading approach, followed by virtual screening of two phytochemical libraries, Ayurvedic (n = 2103 compounds) and Traditional Chinese Medicine (n = 36,043 compounds). ADMET profiling, followed by PBPK modeling in the central body compartment, in a population of 250 non-diseased, 250 cirrhotic and 250 renally impaired people was attempted. ZINC85624912 from Chinese medicinal library showed the highest bioavailability and plasma retention. This is the first attempt to simulate the fate of natural products in the body through PBPK. Dynamics simulation of 20 ns for the top three compounds from both libraries was also performed to validate the stability of the compounds. The obtained information from the current study could aid wet-lab scientists to work on the scaffold of screened drug-like compounds from natural resources and could be useful in our quest for therapy against antibiotic-resistant E. albertii.

Therapeutic target mapping from the genome of Kingella negevensis and biophysical inhibition assessment through PNP synthase binding with traditional medicinal compounds.

Kingella negevensis belongs to the Neisseriaceae family. It is implied that it has significant virulence potential due to RTX toxin production, which can cause hemolysis. It usually colonizes the orophayrynx of pediatric population, along with Kingella kingae but has also been isolated from vagina. Todate no report on its drug targets is present, therefore putative therapeutic targets were identified from its genomic sequence data. Traditional Chinese (n > 36,000) and Indian medicinal compounds (n > 2000) were then screened against its pyridoxine 5'-phosphate synthase, a vital therapeutic target. Prioritized TCM compounds included ZINC02525131, ZINC33833737 and ZINC85486932, and Cadiyenol, 9,11,13-Octadecatrienoic acid and 6-Gingerol from Indian medicinal library. Molecular dynamics simulation of top compounds revealed ZINC02525131 as having best stability for 100 ns, compared to Cadiyenol. ADMET profiling was then done, along with physiologically based pharmacokinetic simulation of these compounds in a population of 200 individuals, for 12 h to see fate of the ingested compound. Additionally, the impact of these compounds in a population with cirrhosis and renal impairment was also simulated. We imply in light of all the studied parameters of safety and bioavailability, etc., that 6-Gingerol from Zingiber officinalis rhizome must be proceeded further for in vitro and in vivo testing for inhibition of K. negevensis.