Exploring optimal drug targets through subtractive proteomics analysis and pangenomic insights for tailored drug design in tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, ranks among the top causes of global human mortality, as reported by the World Health Organization's 2022 TB report. The prevalence of M. tuberculosis strains that are multiple and extensive-drug resistant represents a significant barrier to TB eradication. Fortunately, having many completely sequenced M. tuberculosis genomes available has made it possible to investigate the species pangenome, conduct a pan-phylogenetic investigation, and find potential new drug targets. The 442 complete genome dataset was used to estimate the pangenome of M. tuberculosis. This study involved phylogenomic classification and in-depth analyses. Sequential filters were applied to the conserved core genome containing 2754 proteins. These filters assessed non-human homology, virulence, essentiality, physiochemical properties, and pathway analysis. Through these intensive filtering approaches, promising broad-spectrum therapeutic targets were identified. These targets were docked with FDA-approved compounds readily available on the ZINC database. Selected highly ranked ligands with inhibitory potential include dihydroergotamine and abiraterone acetate. The effectiveness of the ligands has been supported by molecular dynamics simulation of the ligand-protein complexes, instilling optimism that the identified lead compounds may serve as a robust basis for the development of safe and efficient drugs for TB treatment, subject to further lead optimization and subsequent experimental validation.

Fibroblast growth factor 2 is a druggable target against glioblastoma: A computational investigation.

Fibroblast growth factor 2 (FGF2) is a key player in cancer and tissue homeostasis and regulates renewal of several stem cell types. The FGF2 role in malignant glioma is proven and tagged FGF2, a novel druggable target, is used for developing potent drugs against glioblastoma. In this study, Asinex 51412372, Asinex 51217461, and Asinex 51216586 were filtered to show the best binding affinity for FGF2 with binding energy scores of -8.3 kcal/mol, -8.2 kcal/mol, and -7.8 kcal/mol, respectively. The compounds showed chemical interactions with several vital residues of FGF2 along the compound length. The noticeable residues that interacted with the compounds were Arg15, Asp23, Arg63, and Gln105. In dynamic investigation in solution, the FGF2 reported unstable dynamics in the first 100 ns and gained structural equilibrium in the second phase of 100 ns. The maximum root mean square deviation (RMSD) value touched by the systems is 3 Å. Similarly, the residue flexibility of FGF2 in the presence of compounds was within a stable range and is compact along the simulation time length. The compounds showed robust atomic-level stable energies with FGF2, which are dominated by both van der Waals and electrostatic interactions. The net binding energy of systems varies between -40 kcal/mol and -86 kcal/mol, suggesting the formation of strong intermolecular docked complexes. The drug-likeness and pharmacokinetic properties also pointed toward good structures that are not toxic, have high gastric absorption, showed good distribution, and readily excreted from the body. In summary, the predicted compounds in this study might be ideal hits that might be further optimized for structure and activity during experimental studies.

Bacterial Spectrum and Antimicrobial Profile of Pediatric Blood Stream Infection at a Tertiary Care Hospital in Pakistan.

Objectives Blood stream infections (BSIs) are the main cause of morbidity and mortality in children worldwide. The present study was carried out to determine the prevalence of BSI with a focus on the identification of the causative agent of BSI, and to further evaluate the antibiotic susceptibility profile of the causing bacterial pathogens.Methods A cross-section study was carried out at the tertiary care hospital in Peshawar, Pakistan from January to December, 2018. Blood samples were collected in BACTECTM bottles and standard microbiological protocols were applied for the isolation and identification of bacterial strains. The antibiotic susceptibility tests were performed using disc diffusion method as per the 2014 guideline of Clinical Laboratory Standard Institute (CLSI).Results Of 567 blood cultures in total, 111(19.6%) were positive for BSI. Male children were 64 % (71/111) and female children were 36% (40/111). For the causative predominant group of microorganisms, Gram-negative bacteria were identified in 79 (71.1%) isolates, and Gram-positive bacteria in 32 (28.9%) isolates. The common bacteria of isolates were S. typhi (n=35, 31.5%), E. coli (n=19, 17.1%), S. aureus (n=18, 16.2%), K. pneumonia (n=12, 10.8%), and Enterococcus species (n=7, 6.3%). The 36.7% (29/79) isolates of Gram-negative bacteria were ESBL producers, and 61.1% (11/18) of S. aureus isolates were methicillin resistant. Overall, 72.9% isolates were multidrug resistant.Conclusions Gram-negative bacteria were the main cause of pediatric BSIs, where the predominant microorganism was S. typhi. Remarkably, majority of the S. typhi isolates were resistant to ciprofloxacin.