Draft genome sequence of Enterobacter cloacae ST473 harbouring blaCMH-3 isolated from a human patient diagnosed with recurrent bacteriuria in Nigeria.

Enterobacter cloacae is among the most frequently isolated species described in clinical infections and is commonly associated with a multidrug resistance (MDR) phenotype. We present the draft genome sequence of a MDR E. cloacae isolated in Nigeria from the urine sample of an adult male outpatient diagnosed with symptomatic recurrent bacteriuria. The isolate was found to be resistant to ceftriaxone, cefotaxime, cefepime and levofloxacin. Genome analysis revealed the presence of the beta-lactamase chromosomal gene blaCMH-3, which may be responsible for the antibiotic resistance observed in the recurrent E. cloacae urinary tract infection.

Computational drug design of novel COVID-19 inhibitor.

Background: In 2003, the first case of severe acute respiratory syndrome coronavirus (SARS-CoV) was recorded. Coronaviruses (CoVs) have caused a major outbreak of human fatal pneumonia. Currently, there is no specific drug or treatment for diseases caused by SARS CoV 2. Computational approach that adopts dynamic models is widely accepted as indispensable tool in drug design but yet to be exploited in covid-19 in Zaria, Nigeria. In this study, steps were taken to advance on the successful achievements in the field of covid-19 drug, with the aid of in silico drug design technique, to create novel inhibitor drug candidates with better activity. In this study, one thousand human immunodeficiency virus (HIV1) antiviral chemical compounds from www.bindingBD.org were docked on the SARS CoV 2 main protease protein data bank identification number 6XBH (PDB ID: 6XBH) and the molecular docking score were ranked in order to identify the compounds with the highest inhibitory effects, and easy selection for future studies. Results: The docking studies showed some interesting results. Inhibitors with Index numbers 331, 741, and 819 had the highest binding affinity. Similarly, inhibitors with Index number 441, 847, and 46 had the lowest hydrogen bond energy. Inhibitor with index number 331 was reported with the lowest value (- 48.38kCal/mol). Five new compounds were designed from the selected six (6) compounds with the best binding score giving a total of thirty (30) novel compounds. The low binding energy of inhibitor with index no. 847b is unique, as most of the interaction energies are of H-bond type with amino acids (Thr26, Gly143, Ser144, Cys145, Glu166, Gln189, Hie164, Met49, Thr26, Thr25, Thr190, Asn142, Met165) resulting in an overall negative value (-16.31 kCal/mol) making it the best of all the newly designed inhibitors. Conclusions: The novel inhibitor is 2-(2-(5-amino-2-((((3-aminobenzyl)oxy)carbonyl)amino)-5-oxopentanamido)-4-(2-(tert-butyl)-4-oxo-4-(pentan-3-ylamino) butanamido)-3-hydroxybutyl) benzoic acid. The improvement it has over the parent inhibitor is from the primary amine group attached to meta position of first benzene ring and the carboxyl group attached to the ortho position of the second benzene ring. The molecular dynamics studies also show that the novel inhibitor remains stable after the study. This result makes it a better drug candidate against SARS CoV 2 main protease when compared with the co-crystallized inhibitor or any of the 1000 docked inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1186/s42269-022-00892-z.

Zinc Deficiency Elevates Fecal Protein, But Not Electrolyte and Short-Chain Fatty Acid, Levels in Enterotoxigenic Escherichia coli-Induced Diarrhea in Rats.

PURPOSE: To determine the effect of zinc deficiency on fecal protein, electrolyte, and short-chain fatty acid levels in both heat-stable (ST) and heat-labile (LT) enterotoxigenic Escherichia coli (ETEC)-induced diarrhea in rats. METHODS: Albino rats, weighing 100 to 150 g, were divided into 2 groups, with 15 animals each: non-zinc and zinc-deficient. These two groups were sub-divided into three sub-groups with five rats each: control (saline); LT-ETEC; and ST-ETEC. Sodium phytate (30 mmol/L) was added to the animals' water to induce zinc deficiency, while diarrhea was induced using 5×109 ETEC cells/mL. Fecal protein levels were estimated using the Bradford method, while sodium and potassium levels were determined using atomic absorption spectrophotometry. Short-chain fatty acids were measured using gas chromatography-mass spectrometry. RESULTS: Among the non-zinc and zinc-deficient groups, there were significant increases (p=0.04), (p=0.03) in fecal protein concentrations (mg/mL) in the LT-ETEC- (4.50±0.33), (6.50±0.26) and ST-ETEC- (3.85±0.19), (5.98±0.32) induced groups compared to the control groups (2.60±0.52), (3.50±0.11) respectively. Fecal sodium and potassium levels (mg/L) were significantly (p=0.029) increased in non-zinc-deficient rats induced with LT-ETEC (9.35±0.95, 1.05±0.48), and ST-ETEC (9.96±1.02, 1.21±0.45) compared with the control group (8.07±0.44, 0.47±0.17) but the increase were not statistically significant (p=0.059) in the zinc deficient rat groups. Fecal acetate and propionate levels (mg/g) significantly (p=0.032) increased when induced with LT-ETEC and ST-ETEC in non-zinc and zinc-deficient groups compared with the control groups. CONCLUSION: Zinc deficiency among rats with ETEC-induced diarrhea elevated fecal protein loss but may not have an effect on fecal sodium, potassium and short-chain fatty acid levels.

Computer-aided modeling of triazole analogues, docking studies of the compounds on DNA gyrase enzyme and design of new hypothetical compounds with efficient activities.

The increasing problem of multi-drug resistant-tuberculosis has focused attention on developing new drugs that are not only active against drug-resistant tuberculosis, but also shorten the lengthy therapy. Therefore, this work employs the application of modeling technique to predict the inhibition activities of some prominent compounds which been reported to be efficient against Mycobacterium tuberculosis. To accomplish the purpose of this work, multiple regression and genetic function approximation were adopted to create the model. The established model was swayed with topological descriptors; MATS7s, SpMin4_Bhv, TDB3v and RDF70v. More also, interactions between the compounds and the target protein 'DNA gyrase' were evaluated via molecular docking approach utilizing the PyRx and discovery studio simulation software. Based on the docking analysis, compound 20 has the most noticeable binding affinity of -16.5 kcal/mol. Therefore, compound 20 served as a reference structural template and insight to design fourteen novel hypothetical agents with more prominent anti-tubercular activities. More also, compound 20j was observed with the highest activity among the designed compounds with a prominent binding affinity of -24.3 kcal/mol. Therefore, this research recommends in-vivo, in-vitro screening and pharmacokinetic properties to be carried out in order to determine the toxicity of the designed compounds.Communicated by Ramaswamy H. Sarma.

Trends in Empirical Treatment of Hospitalized Children with Acute Gastroenteritis in Nigeria.

BACKGROUND: Acute gastroenteritis is a common infectious disease with a high rate of morbidity and mortality in children below five years of age. Appropriate empirical treatment is therefore vital for reducing the incidence of the disease. OBJECTIVE: This study aimed at determining the trends in the empirical treatment of hospitalized children with acute gastroenteritis. METHODS: The study involved the data analysis of 88 medical folders of children who were diagnosed with gastroenteritis from January to February 2020 (a period of gastroenteritis yearly outbreak) in Mile 4 Hospital Abakaliki, Ebonyi State, Nigeria. Socio-demographic data and administered antibiotics data were collected. RESULTS: Out of the 88 children, a total of 54 (61%) children were males, while 34 (39%) were females. The ages of the children ranged between 1-51 months, while the mean age was seen at 14 months. About 58 (66%) were diagnosed with acute gastroenteritis alone, with children aged 7-12 months recording higher numbers [25 (28%)]. Severe dehydration was seen as the most common morbidity of children with acute gastroenteritis. The guardians/parents of these children stayed at home for an average of 3 days (1-6 days) before visiting the hospital. The children were treated for an average of 5 days (2-9 days) in the hospital. The most singly used antibiotics was ciprofloxacin [31 (35%)] followed by a combination of ciprofloxacin and ceftriaxone [21 (24%)]. About 12 (14%) of the children were treated using a single dose of the antimalarial drug while 10 (11%) were treated in double combination therapy. The lowest duration in hospitalization (4 days) was seen in the use of a single dose regimen, while the highest hospitalization time (6 days) was seen in the use of a triple dose regimen. CONCLUSION: The best empirical treatment of acute gastroenteritis may involve the use of ciprofloxacin alone and its combination with ceftriaxone. The severity of gastroenteritis may also be exacerbated with malaria.

Homology modeling and molecular docking simulation of some novel imidazo[1,2-a]pyridine-3-carboxamide (IPA) series as inhibitors of Mycobacterium tuberculosis.

BACKGROUND: Tuberculosis (TB) remains a serious global health challenge that is caused by Mycobacterium tuberculosis and has killed numerous people. This necessitated the urgent need for the hunt and development of more potent drugs against the fast-emerging extensively drug-resistant (XDR) and multiple-drug-resistant (MDR) M. tuberculosis strains. Mycobacterium tuberculosis cytochrome b subunit of the cytochrome bc1 complex (QcrB) was recognized as a potential drug target in M. tuberculosis (25618/H37Rv) for imidazo[1,2-a]pyridine-3-carboxamides whose crystal strucuture is not yet reported in the Protein Data Bank (PDB). The concept of homology modeling as a powerful and useful computational method can be applied, since the M. tuberculosis QcrB protein sequence data are available. RESULTS: The homology model of QcrB protein in M. tuberculosis was built from the X-ray structure of QcrB in M. smegmatis as a template using the Swiss-Model online workspace. The modeled protein was assessed, validated, and prepared for the molecular docking simulation of 35 ligands of N-(2-phenoxy)ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) to analyze their theoretical binding affinities and modes. The docking results showed that the binding affinity values ranged from - 6.5 to - 10.1 kcal/mol which confirms their resilience potency when compared with 6.0kcal/mol of isoniazid standard drug. However, ligands 2, 7, 22, 26, and 35 scored higher binding affinity values of - 9.60, - 9.80, - 10.10, - 10.00, and - 10.00 kcal/mol, and are respectively considered as the best ligands among others with better binding modes in the active site of the modeled QcrB protein. CONCLUSION: The information derived in this research revealed some potential hits and paved a route for structure-based drug discovery of new hypothetical imidazo pyridine amide analogs as anti-tubercular drug candidates.

Quantitative structure-activity relationship (QSAR) and design of novel ligands that demonstrate high potency and target selectivity as protein tyrosine phosphatase 1B (PTP 1B) inhibitors as an effective strategy used to model anti-diabetic agents.

Diabetes and obesity have increased dramatically in recent decades worldwide. Diabetes mainly emerged as a major health care burden disease in both the US and other industrialized countries, among which type II diabetes is the most common. Discovering new and effective treatments for diabetes is currently a high international health priority. In the present study a computational technique was used to model 97 compounds with PTP-1B inhibitory activity, in order to demonstrate the Quantitative structure-activity relationship (QSAR) of these compounds a genetic function approximation (GFA) algorithm was applied to pick the best descriptors and multiple linear regression (MLR) was used to establish a relationship between the PTP-1B inhibitory activity of these compounds and the best molecular descriptors. This QSAR study allowed investigating the influence of very simple and easy-to-compute descriptors in determining biological activities, which shed light on the key factors that aid in the design of novel potent molecules using computer-aided drug design tools.

Co-administration of Selenium Nanoparticles and Metformin Abrogate Testicular Oxidative Injury by Suppressing Redox Imbalance, Augmenting Sperm Quality and Nrf2 Protein Expression in Streptozotocin-Induced Diabetic Rats.

Selenium nanoparticles (SeNPs) and metformin (Met) elicit individually protective effects against testicular oxidative injury in diabetic rats. However, the combined effects of both compounds have not been investigated. We investigated the effects of SeNPs and Met individual/co-treatment on testicular oxidative injury in diabetic rats. Diabetes was induced by a single intraperitoneal administration of streptozotocin (STZ-40 mg/kg bwt). The rats were equally divided into 6 groups: Group one-non-diabetic; group two-diabetic untreated; and group six-non-diabetic received citrate buffer (2 mL/kg bwt), while group three, four, and five received SeNPs (0.1 mg/kg bwt), Met (50 mg/kg bwt), and SeNPs/Met combined respectively, for 42 days. Results revealed that SeNPs, as well as Met treatment significantly (p < 0.001), lowered blood glucose levels and improved relative organ weights in treated rats than those of the untreated group. Moreover, a synergistic effect was observed in the co-administration group. Additionally, combined treatment elicited better effect, in augmenting the pituitary and testicular hormone (LH, FSH, prolactin, and testosterone) levels, marker enzymes/protein associated with steroidogenesis (3-ßHSD, 17-ßHSD, and StAR protein), and sperm functional parameters than those of individual treatment groups, when compared with control. Furthermore, the combinatorial effects of SeNPs and Met surpassed their influence in attenuating testicular oxidative stress/inflammation and upregulation of Nrf2 protein expression in diabetic rats when compared with control. Overall, normal rats, co-treated with SeNPs and Met, did not reveal any deleterious effect. Therefore, SeNPs and Met combined treatment may better improve testes function in diabetic conditions than an individual regimen.

Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats.

Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and Drug Administration in 1977. However, TAM therapy is accompanied with hepatotoxicity - a source of worry to clinicians. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM hepatotoxicity. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced hepatotoxicity in female Wistar rats. Rats were subjected to oral pretreatment of Zn (100 mg/kg body weight (b.w.)/day) for 14 days against hepatic toxicity induced by single intraperitoneal administration of TAM (50 mg/kg b.w.) on day 13. TAM markedly elevated serum liver enzymes, whereas total protein and albumin considerably reduced. TAM caused prominent depletion of hepatic-reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity. Also, TAM significantly increased malondialdehyde (MDA) level. Further, it raised liver levels of tumor necrosis factor-α (TNF-α), interleukin-1ß, (IL-1ß), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by the liver histopathological alterations. The mechanistic inflammatory expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-ĸB), and expression of caspase-3 protein prominently increased. Zinc supplementation significantly modulated serum liver function markers, antioxidant enzymes, and GSH and MDA levels. Zinc downregulated the expression of cytokines, NO, iNOS, NF-ĸB and caspase-3, and ameliorated histopathological changes. Zinc protects against TAM-induced hepatotoxicity; it may serve as an adjuvant supplement for female patients undergoing TAM chemotherapy.

Modulatory role of rutin on 2,5-hexanedione-induced chromosomal and DNA damage in rats: validation of computational predictions.

The aim of this study was to evaluate the potentials of rutin on 2,5-hexanedione-induced toxicities. Two successive phases were involved using in silico and in vivo approaches. The in silico was adopted for potential oral toxicity and docking. The in vivo was carried-out in two stages for two weeks; the ameliorative (stage 1, first week), preventive, and curative studies (stage 2, extended to second week). In stage 1, rats were divided into four groups of seven each (distilled water, 3% (v/v) 2,5-hexanedione, 10 mg/kg rutin, and co-administration). In stage 2, the experimental groups were given either rutin or 2,5-hexanedione and treated in reverse order. Lipid peroxidation, protein carbonyl, and DNA fragmentation in tissues and bone marrow cells micronucleus were determined. The predicted Median lethal dose (LD50) of >5000 mg/kg and toxicity class of five (5) indicates the safety of rutin when orally administered. 2,5-Hexanedione comfortably docked in to the active sites of SOD (-22.857Kcal/mol; KI = 0.9621 µM), GPx (-11.2032Kcal/mol; KI = 0.9813 µM), and CAT (-16.446Kcal/mol; KI = 0.9726 µM) with strong hydrogen bond and hydrophobic interactions. However, only strong hydrophobic interaction was observed in the case of DNA (-3.3296Kcal/mol; KI = 0.9944). In vivo findings revealed deleterious effects of 2,5-hexanedione through induction of oxidative and chromosomal/DNA damage characterized by higher level of malondialdehyde, micronuclei formations, and DNA fragmentation. These have invariably, validates the findings from in silico experiments. Furthermore, rutin was able to ameliorate, protect, and reverse these effects, and was relatively non-toxic corroborating toxicity predictions. Rutin exhibited counteractive effects on 2,5-hexanedione-induced oxidative, chromosomal, and DNA damage.

A Derived QSAR Model for Predicting Some Compounds as Potent Antagonist against Mycobacterium tuberculosis: A Theoretical Approach.

Development of more potent antituberculosis agents is as a result of emergence of multidrug resistant strains of M. tuberculosis. Novel compounds are usually synthesized by trial approach with a lot of errors, which is time consuming and expensive. QSAR is a theoretical approach, which has the potential to reduce the aforementioned problem in discovering new potent drugs against M. tuberculosis. This approach was employed to develop multivariate QSAR model to correlate the chemical structures of the 2,4-disubstituted quinoline analogues with their observed activities using a theoretical approach. In order to build the robust QSAR model, Genetic Function Approximation (GFA) was employed as a tool for selecting the best descriptors that could efficiently predict the activities of the inhibitory agents. The developed model was influenced by molecular descriptors: AATS5e, VR1_Dzs, SpMin7_Bhe, TDB9e, and RDF110s. The internal validation test for the derived model was found to have correlation coefficient (R2) of 0.9265, adjusted correlation coefficient (R2 adj) value of 0.9045, and leave-one-out cross-validation coefficient (Q_cv∧2) value of 0.8512, while the external validation test was found to have (R2 test) of 0.8034 and Y-randomization coefficient (cR_p∧2) of 0.6633. The proposed QSAR model provides a valuable approach for modification of the lead compound and design and synthesis of more potent antitubercular agents.

Modulation of the Lipid Profile, Hepatic and Renal Antioxidant Activities, and Markers of Hepatic and Renal Dysfunctions in Alloxan-Induced Diabetic Rats by Virgin Coconut Oil.

BACKGROUND: Research studies that holistically investigated the effect of administration of Virgin Coconut Oil (VCO) on diabetic humans or animals are limited in literature. OBJECTIVE: To investigate the effect of administration of VCO on lipid profile, markers of hepatic and renal dysfunction, and hepatic and renal antioxidant activities of alloxan induced diabetic rats. METHODS: Twenty-four male albino rats were used, and they were divided into four groups of six rats each. Group 1 (Normal Control, NC) received distilled water (1 mL/kg); Group 2 (VCO Control) received VCO (5 mL/kg); Group 3 (Diabetic Control, DC) received distilled water (1 mL/kg); Group 4 (Test Group, TG) received 5 ml/kg of VCO. RESULTS: There were no significant differences in blood glucose, body weights, relative liver weights, relative kidney weights, hepatic and renal Superoxide Dismutase (SOD) activities, Malondialdehyde (MDA), albumin, aspartate Amino Transaminase (AST), alanine Amino Transaminase (ALT), Alkaline Phosphatase (ALP), urea, creatinine, uric acid, total cholesterol, triacylglycerol, Very Low Density Lipoprotein cholesterol (VLDL) and Low Density Lipoprotein cholesterol (LDL) concentrations; significant increases in renal Glutathione (GSH), hepatic catalase, Glutathione Peroxidase (GPx) and GSH but significant reduction in renal GPx and catalase activities of VCO control group compared with NC group. There were significant increases in blood glucose, relative liver and kidney weights, hepatic GPx, hepatic and renal MDA concentration, ALP, AST, ALT, urea, creatinine, uric acid, triacylglycerol, total cholesterol, LDL and VLDL concentrations; and significant decreases in body weight, hepatic SOD and GSH activities and albumin concentration but no significant difference in hepatic catalase activity of DC group compared with NC group. Administration of VCO to diabetic rats positively modulated these parameters compared with the diabetic control. CONCLUSION: The study showed the potentials of VCO in the management of hyperlipidemia, renal and hepatic dysfunctions imposed by hyperglycemia and by oxidative stress in diabetic rats.

Comparative study on the nutrients, heavy metals and pesticide composition of some locally produced and marketed rice varieties in Nigeria.

The nutrients, heavy metals and pesticide concentrations of an imported (Gold) and three locally produced and marketed rice varieties (Samples B-mass, C-R8 and D-CP) in Nigeria were investigated using standard techniques. All the rice varieties contained considerable amounts of moisture, ash, protein, lipid and carbohydrate but were low in crude fibre. The local rice varieties contained higher (P < 0.05) amounts of tryptophan and tyrosine than the imported rice. Sample C had the highest amino acids contents compared with other rice varieties. The threonine contents of the control and sample B were higher than WHO standards. Lead and mercury were not detected in all the rice varieties while the levels of cadmium, arsenic, chromium and thallium were within permissible range. The rice varieties contained considerable amounts of selenium, calcium, iron, manganese, zinc, phosphorous, boron, cobalt, Vitamins A, D, B6, thiamine, riboflavin, niacin and cobalamin with insignificant amounts of pesticide residues.