Fragment-based virtual screening identifies novel leads against Plasmepsin IX (PlmIX) of Plasmodium falciparum: Homology modeling, molecular docking, and simulation approaches.

Despite continuous efforts to develop safer and efficient medications, malaria remains a major threat posing great challenges for new drug discovery. The emerging drug resistance, increased toxicities, and impoverished pharmacokinetic profiles exhibited by conventional drugs have hindered the search for new entities. Plasmepsins, a group of Plasmodium-specific, aspartic acid protease enzymes, are involved in many key aspects of parasite biology, and this makes them interesting targets for antimalarial chemotherapy. Among different isoforms, PlmIX serves as an unexplored antimalarial drug target that plays a crucial role along with PlmV and X in the parasite's survival by digesting hemoglobin in the host's erythrocytes. In this study, fragment-based virtual screening was performed by modeling the three-dimensional structure of PlmIX and predicting its ligand-binding pocket by using the Sitemap tool. Screening identified the fragments with the XP docking score ≤ -3 kcal/mol from the OTAVA General Fragment Library (≈16,397 fragments), and the selected fragments were chosen for ligand breeding. The resulting ligands (≈69,858 ligands) were subsequently subjected to filtering based on the QikProp properties along with carcinogenicity testing performed using CarcinoPred-EL and then docked in the SP (≈14,078 ligands) as well as XP mode (≈3,104 ligands), and compared with that of control ligands 49C and I0L. The top-ranked ligands were taken further for the calculation of the free energy of binding using Prime MM-GBSA. Overall, a total of six complexes were taken further for MD simulation studies performed at 100 ns to attain a better understanding of the binding mechanisms, and compounds 3 and 4 were found to be the most efficient ones in silico. The analysis of compound 3 revealed that the carbonyl group present in position 1 on the isoindoline moiety (Arg554) was responsible for inhibitory activity against PlmIX. However, the analysis of compound 4 revealed that the amide linkage sandwiched between the phenyl ring and isoquinoline moiety (Lys555 and Ser226) as well as carbonyl oxygen of the carbamoyl group present at position 2 of the pyrazole ring (Gln222) were responsible for PlmIX inhibitory activity, owing to their crucial interactions with key amino acid residues.

Evaluation to Determine Antibiotic Resistance Reduction in Gram-Negative Bacteria from 2019 to 2021 by the Saudi Arabia National Plan.

Introduction: The main objective of this study was to investigate the three-year evaluation of antibiotic resistance (AR) of multi-drug-resistant organisms and extended-spectrum beta-lactamase (ESBL)-resistant rate of gram-negative bacteria in one of the largest hospitals by the Saudi Arabia Nation Plan. Methods: This study was conducted in the Department of Laboratory Medicine, in a private hospital in Riyadh City, Saudi Arabia, from January 2019 to December 2021 in 120-bed private hospitals. A total of 4700 gram-negative isolated organisms were obtained from the various specimens of the patients, and antibiotic sensitivity tests were performed. According to the manufacturer's instructions, the inoculum prepared was applied to two test cards, one for the identification system VITEK 2 ID-GNB and another for susceptibility testing antimicrobial susceptibility testing (AST) No. 12. Result: The most common gram-negative bacteria isolated was Escherichia coli (2706/4700; 57.57%), followed by Klebsiella pneumoniae (905/4700; 19.25%) and Pseudomonas aeruginosa (395/4700; 8.40%). Escherichia coli's highest AR reduction was reported for cefotaxime (CTX) of 29% (295/1018; 29%, 172/818; 21%, 0/870; 0%) for 2019, 2020, and 2021, respectively. Except for Salmonella species, which displayed enhanced AR, the ESBL and multidrug-resistant (MDR) rates decreased significantly (p 0.05) for most bacteria. Conclusion: This study helps to understand the maximum number of gram-negative bacteria susceptible to the Saudi National Action Plan (SNAP) to decrease the prevalence of AR, ESBL, and MDR. To comprehensively understand SNAP's effectiveness, other trials involving gram-positive bacteria should be considered.

Leprosy Classification, Clinical Features, Epidemiology, and Host Immunological Responses: Failure of Eradication in 2023.

Leprosy is of big concern in the medical fraternity. Leprosy is also known as Hansen's disease. It is a curable communicable disease that remains prevalent in most countries all over the globe. It is a chronic granulomatous infection commonly caused by Mycobacterium leprae and Mycobacterium lepromatosis, which mainly show an effect on the skin and peripheral nerves. To control the disease and minimize the impact of the disease, much effort has been put into it for decades. Nearly 0.2 million fresh cases were documented in 2017 worldwide in spite of being declared "eradicated" by the WHO in the year 2000. However, impressive achievements have been made in several countries, including India; still, we are lagging behind the ultimate goal of the final disappearance of leprosy. Extensive migration is a crucial element that may transmit leprosy to unaffected areas. Additionally, there are several areas in the USA where person-to-person leprosy transmission has been reported without a prior history of exposure. Recently, WHO instigated a new Global Leprosy Strategy 2021-2030, termed "Towards Zero Leprosy." In this article, we review the clinical features, leprosy epidemiology, transmission, classification, host immunological response, and diagnostic challenges.

Association of genetic polymorphisms in DNA repair genes ERCC2 Asp312Asn (rs1799793), ERCC2 Lys 751 Gln (rs13181), XRCC1 Arg399 Gln (rs25487) and XRCC3 Thr 241Met (rs861539) with the susceptibility of lung cancer in Saudi population.

This study demonstrated the association of polymorphisms in ERCC2 (Asp312Asn) rs1799793, ERCC2 (Lys751Gln) rs13181, XRCC1 (Arg399Gln) rs25487 and XRCC3(Thr241Met) rs861539 polymorphisms with a susceptibility of lung cancer (LC) onset in the Saudi population. The study was performed on 134 LC patients and 270 controls. The data revealed that there was no significant association of LC with subtype squamous cell carcinoma (SCC), small cell lung cancer (SCLC) and adenocarcinoma with the ERCC2 rs1799793 polymorphism. The data showed that the CC genotype for ERCC2 rs13181, the AA genotype for XRCC1 rs25487, and the genotype TT for XRCC3 rs861539 were significantly associated with SCC susceptibility (p < 0.05). Similarly, the CC genotype for ERCC2 rs13181 and the AA genotype for XRCC1 rs25487 were significantly associated with adenocarcinoma susceptibility (p < 0.05). Whereas, the TT genotype for XRCC3 rs861539 was significantly associated with SCLC susceptibility (p = 0.005). In total, significant association of LC susceptibility was found in the following combination models of recessive genotypes: AC heterozygous for ERCC2 rs13181 + AA homozygous for XRCC1 rs25487, CC homozygous for ERCC2 rs13181 + GA heterozygous for rs25487, CC homozygous for rs13181 + AA homozygous for XRCC1 rs25487, CC homozygous for ERCC2 rs13181 + TT homozygous for XRCC3 rs861539, GA heterozygous for XRCC1 rs25487 + CT heterozygous for XRCC3 rs861539, GA heterozygous for XRCC1 rs25487 + TT homozygous for XRCC3 rs861539, AA homozygous for XRCC1 rs25487 + CT heterozygous for XRCC3 rs861539, AA homozygous for XRCC1 rs25487+ TT homozygous for XRCC3 rs861539. These data clearly demonstrated that the combination of recessive genotypes may be associated with susceptibility of LC onset (p < 0.05). In short, the data indicated that DNA repair genes increase LC risk via gene-gene interaction rather than independent variants.

ATP2B1 genotypes rs2070759 and rs2681472 polymorphisms and risk of hypertension in Saudi population.

This study examined an association of ATP2B1 gene polymorphism and hypertension in the Saudi population. The 246 hypertensive cases and 300 healthy human controls were genotyped. The results showed that genotypes rs.207075 (CA + AA) [p = 0.05; OR: 95% CI, 1.5:(1.0 to 2.4) and p = 0.001, OR: 95% CI, 2.4: (1.5 to 4.0) and rs2681472 (CT + TT) [p = 0.05; OR: 95% CI, 1.5 (1.0 to 2.4) and p = 0.006 OR: 95% CI, 2.0 (1.2 to 3.1) respectively] associated with the risk of hypertension. Cases carrying the recessive models: [(CA + AA)/(CT + TT)] and [(AA)/(TT)] genotypes confer a strong susceptibility risk of hypertension [p = 0.002; OR: (95%CI) 1.8 (1.2 to 2.6) and p = 0.001; OR: (95%CI) 2.6 (1.5 to 4.7) respectively]. However, cases with body-mass-index (BMI)<25, carrying homozygous mutant genotypes [AA, rs2070759, p = 0.007; OR: (95%CI) 2.75(1.37 to 5.5) and (TT, rs2681472, p = 0.05; OR: (95%CI) 1.96 (1.03 to 3.72)] as well as A allele of rs2070759 [p = 0.006; OR: (95%CI) 1.62 (1.16 to 2.25)] and T allele of rs2681472, p = 0.04, 1.43(1.03 to 1.98)] showed a significant association with high risk of hypertension. In short, a significant association between ATP2B1 gene polymorphism and risk of hypertension was noticed. In addition, individuals carrying recessive genotypes have greater risk in developing hypertension than those carrying dominant genotypes. Moreover, cases with high-risk BMI associated with ATP2B1 variants may play a critical role in developing hypertension.Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2021.1973034 .

Three Years of Evaluation to Determine Reduction of Antibiotic Resistance in Gram-Negative Bacteria by the Saudi National Action Plan.

BACKGROUND: Bacterial antibiotic resistance (AR) is a primary public health concern. In 2017, the Saudi National Action Plan (SNAP) implemented several strategies to overcome AR. Here, to better understand the effectiveness of that plan, we evaluated the rates of AR, extended-spectrum beta-lactamase (ESBL) positivity, and multi-drug resistance (MDR) among gram-negative bacteria in a private Saudi hospital. METHODS: This retrospective study included all patients with a confirmed diagnosis of gram-negative bacterial infection from January 2017 to December 2019. Identification of bacterial strains was performed using VITEK 2 ID-GNB cards, while AR, ESBL, and MDR were determined using AST-No. 12 cards, both used as recommended by the manufacturer. Cards were loaded into a VITEK 2 system for examination. RESULTS: A total of 4760 isolated gram-negative bacteria were collected. The most isolated organism was Escherichia coli, with 2585/4760 (54.30%) strains, and the least was Providencia stuartii, with 55/4760 (1.16%) strains. A total of 1328/4760 (27.90%) clinical isolates were ESBL-positive, and 851/4760 (17.88%) possessed MDR. Escherichia coli was also the most frequently isolated as having ESBL activity and MDR, with 772/1328 (58.13%) and 292/851 (34.31%) isolates, respectively. Between 2017 and 2019, the rates of ESBL and MDR were significantly reduced (p < 0.05) for most bacteria, except for Salmonella species, which showed increased resistance to antibiotics. CONCLUSION: Our findings revealed that the rates of AR, ESBL, and MDR reduced over time, which suggests the SNAP is effective at overcoming AR risk.

Extraneural metastasis of an ependymoma: a rare occurrence.

Extraneural metastases of ependymoma are very rare, and have been reported in the lungs, lymph nodes, pleura, mediastinum, liver, diaphragmatic muscle, and bone. We describe the radiological findings of pathologically proven lung metastases from an anaplastic ependymoma. The tumor which arose in the posterior fossa was first diagnosed in 2007 when first surgical resection was performed outside our institute. Multiple operations were performed after that due to tumor relapse. Multiple lung nodules were discovered incidentally during a VP shunt survey. Biopsy from the lung nodules displayed identical histomorphology to the primary brain tumor.