Repurposing of Compounds from Streptomyces spp. as Potential Inhibitors of Aminoacyltransferase FemA: An Essential Drug Target against Drug-resistant Staphylococcus aureus.

BACKGROUND: Drug-resistant Staphylococcus aureus represents a substantial healthcare challenge worldwide, and its range of available therapeutic options continues to diminish progressively. Thus, this study aimed to identify potential inhibitors against FemA, a crucial protein involved in the cell wall biosynthesis of S. aureus. MATERIALS AND METHODS: The screening process involved a comprehensive structure-based virtual screening on the StreptomDB database to identify ligands with potential inhibitory effects on FemA using AutoDock Vina. The most desirable ligands with the highest binding affinity and pharmacokinetic properties were selected. Two ligands with the highest number of hydrogen bonds and hydrophobic interactions were further analyzed by molecular dynamics (MD) using the GROMACS version 2018 simulation package. RESULTS: Six H-donor conserved residues were selected as protein active sites, including Arg- 220, Tyr-38, Gln-154, Asn-73, Arg-74, and Thr-24. Through virtual screening, a total of nine compounds with the highest binding affinity to the FemA protein were identified. Frigocyclinone and C21H21N3O4 exhibited the highest binding affinity and demonstrated favorable pharmacokinetic properties. Molecular dynamics analysis of the FemA-ligand complexes further indicated desirable stability and reliability of complexes, reinforcing the potential efficacy of these ligands as inhibitors of FemA protein. CONCLUSION: Our findings suggest that Frigocyclinone and C21H21N3O4 are promising inhibitors of FemA in S. aureus. To further validate these computational results, experimental studies are planned to confirm the inhibitory effects of these compounds on various S. aureus strains. Combining computational screening with experimental validation contributes valuable insights to the field of drug discovery in comparison to the classical drug discovery approaches.

Introduction of Novel Drug Targets against Staphylococcus aureus and Proposing Putative Inhibitors against Adenine N1 (m1A22)-tRNA Methyltransferase (TrmK) using Computer-aided Drug Discovery.

BACKGROUND: Nowadays, the emergence of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) strains has dramatically restricted the treatment options against this microorganism. AIM: In this study, we aimed to discover new drug targets and inhibitors against S. aureus. METHODS: This study consists of two major sections. In the upstream evaluation, after a comprehensive coreproteome analysis, essential cytoplasmic proteins with no similarity to the human proteome were selected. Then the S. aureus metabolome-specific proteins were selected, and novel drug targets were identified using the DrugBank database. In the downstream analysis, a structure-based virtual screening approach was performed to reveal potential hit compounds against adenine N1 (m(m1A22)-tRNA methyltransferase (TrmK) using the StreptomeDB library and AutoDock Vina software. The compounds with a binding affinity > -9 kcal/mol were analyzed based on ADMET properties. Finally, the hit compounds were selected based on Lipinski's rule of five (RO5). RESULTS: Three proteins, including glycine glycosyltransferase (FemA), TrmK, and heptaprenyl pyrophosphate synthase subunit A (HepS1), were selected as feasible and promising drug targets based on PDB file availability and their essential role in the survival of the S. aureus. Finally, seven hit compounds, including Nocardioazine_ A, Geninthiocin_D, Citreamicin_delta, Quinaldopeptin, Rachelmycin, Di-AFN_A1 and Naphthomycin_ K were introduced against the binding cavity of TrmK, as a feasible drug target. CONCLUSION: The results of this study provided three feasible drug targets against S. aureus. In the following, seven hit compounds were introduced as potential inhibitors of TrmK, and Geninthiocin_D was identified as the most desirable agent. However, in vivo and in vitro investigations are needed to confirm the inhibitory effect of these agents on S. aureus.

The combination of CipA and PBP-7/8 proteins contribute to the survival of C57BL/6 mice from sepsis of Acinetobacter baumannii.

Due to the emergence of multi-drug resistant Acinetobacter baumannii strains, there is an urgent need to develop several new strategies to control this bacterium. In this context, vaccination may be the best approach to reduce the morbidity and mortality associated with MDR isolates in vulnerable groups. Serum resistance factors have a key role in the pathogenesis of A. baumannii and can be considered as potential vaccine candidates. This project aimed to evaluate the immunological reactivity of CipA and PBP-7/8 as two serum resistance factors in a combination form against sepsis infections of A. baumannii. Recombinant proteins were obtained and immunological evaluations were performed against sepsis infection in the C57BL/6 mouse model. The data showed a statistically significant increase in total IgG levels in all three immunization regimens (CipA, PBP-7/8, and CipA + PBP-7/8) compared to the control group. The ratios of IgG2c/IgG1 in the CipA, PBP-7/8, and CipA + PBP-7/8 schedules were 8.7, 46.50, and 33.29, respectively. It appears that the immunization schedules developed a strong polarized Th1 response. The cytokine profiles of the three plans showed that IFN-γ was highly concentrated in the combination plan. However, the highest concentration of IL-17 belonged to the PBP-7/8 plan. In conclusion, the data of total IgG, survival rates and splenic bacterial loads showed that the CipA + PBP-7/8 plan was more effective than each protein individually.

Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis among women with genitourinary infection and pregnancy-related complications in Tehran: A cross-sectional study.

The present study investigates the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) among women with genitourinary infection and pregnancy-related complications in Tehran. It also evaluates the demographic information, symptoms, and sequelae. Endocervical samples were obtained over a period of eight months from 360 women including 180 symptomatic patients and 180 patients with pregnancy-related complications and infertility. CT, NG, and TV were detected in 10.8%, 6.9%, and 8.3% of all patients, respectively. The prevalence of CT, NG, and TV among women in the symptomatic group was 11.1%, 7.2%, and 13.3%, respectively, and among women with pregnancy-related complications and infertility was 10.6%, 6.7%, and 3.3%, respectively. Associations between chlamydia and ectopic pregnancy (p = 0.001), and infertility (p < 0.001) were observed. Abortion (p = 0.008), infertility (p = 0.005), and ectopic pregnancy (p < 0.001) were associated with gonorrhea. Abnormal vaginal discharge (p = 0.02) and vulvar itching (p = 0.02) were associated with trichomoniasis. Overall, the prevalence rates of CT, NG, and TV were high in these patient groups. These high prevalences suggest that screening programs are required to reduce the burden of these sexually transmitted infections and their effects on genitourinary symptoms, pregnancy-related complications, and infertility.