Antiviral activity of astragaloside II, astragaloside III and astragaloside IV compounds against dengue virus: Computational docking and in vitro studies.

This study was aimed to identify the phytocompounds possessing anti-dengue virus activity using in silico and in vitro approaches. A total of 7000 phytocompounds were virtually screened against protein targets (envelope, NS2b/NS3, and NS5) of dengue virus using iGEMDOCK and individually docked using Maestro 10.7 module of Schrödinger software. In vitro cytotoxicity and antiviral studies were performed using vero cell line. Finally, three phytocompounds namely astragaloside II, astragaloside III, and astragaloside IV were screened based on their highest binding energy values against protein targets. Astragaloside III exhibited the highest interaction energy value of -8.718 kcal/mol and -8.447 kcal/mol against envelope, and NS2b/NS3 targets, respectively. Astragaloside IV exhibited -7.244 kcal/mol against SAM site, and -9.179 kcal/mol against RNA cap site of NS5 targets. In silico ADMET analysis revealed that astragaloside II, III, and IV were non-mutagenic and non-carcinogenic in nature and these compounds were also non-toxic to vero cells upto 1000 µg/mL. Against dengue virus serotype 3, astragaloside II exhibited substantial antiviral activity at the concentration of 1.56 µg/mL followed by astragaloside III at 6.25 µg/mL and astragaloside IV at 12.5 µg/mL. Also, against dengue serotype 1, astragaloside II showed the maximum antiviral activity at 1.56 µg/mL followed by astragaloside III and IV at 3.125 µg/mL. This study concludes that astragaloside II, III, and IV compounds had potential in vitro anti-dengue virus activity.

Computational selection of flavonoid compounds as inhibitors against SARS-CoV-2 main protease, RNA-dependent RNA polymerase and spike proteins: A molecular docking study.

An outbreak of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been recognized as a global health concern. Since, no specific antiviral drug is proven effective for treatment against COVID-19, identification of new therapeutics is an urgent need. In this study, flavonoid compounds were analyzed for its inhibitory potential against important protein targets of SARS-CoV-2 using computational approaches. Virtual docking was performed for screening of flavonoid compounds retrieved from PubChem against the main protease of SARS-CoV-2 using COVID-19 docking server. The cut off of dock score was set to >-9 kcal/mol and screened compounds were individually docked against main protease, RNA-dependent RNA polymerase, and spike proteins using AutoDock 4.1 software. Finally, lead flavonoid compounds were subjected to ADMET analysis. A total of 458 flavonoid compounds were virtually screened against main protease target and 36 compounds were selected based on the interaction energy value >-9 kcal/mol. Furthermore, these compounds were individually docked against protein targets and top 10 lead compounds were identified. Among the lead compounds, agathisflavone showed highest binding energy value of -8.4 kcal/mol against main protease, Albireodelphin showed highest dock score of -9.8 kcal/mol and -11.2 kcal/mol against RdRp, and spike proteins, respectively. Based on the high dock score and ADMET properties, top 5 lead molecules such as Albireodelphin, Apigenin 7-(6″-malonylglucoside), Cyanidin-3-(p-coumaroyl)-rutinoside-5-glucoside, Delphinidin 3-O-beta-D-glucoside 5-O-(6-coumaroyl-beta-D-glucoside) and (-)-Maackiain-3-O-glucosyl-6″-O-malonate were identified as potent inhibitors against main protease, RdRp, and spike protein targets of SARS-CoV-2. These all compounds are having non-carcinogenic and non-mutagenic properties. This study finding suggests that the screened compounds include Albireodelphin, Apigenin 7-(6″-malonylglucoside), Cyanidin-3-(p-coumaroyl)-rutinoside-5-glucoside, Delphinidin 3-O-beta-D-glucoside 5-O-(6-coumaroyl-beta-D-glucoside) and (-)-Maackiain-3-O-glucosyl-6″-O-malonate could be the potent inhibitors of SARS-CoV-2 targets.

Occurrence of extended-spectrum ß-lactamase, AmpC, and carbapenemase-producing genes in gram-negative bacterial isolates from human immunodeficiency virus infected patients.

BACKGROUND: Progressive decline of immune response in HIV patients makes them susceptible to frequent bacterial infections. High usage of antibiotics influences the emergence of multidrug-resistant bacteria and worsens the clinical outcomes. In this study, the occurrence of drug-resistant genes in Gram-negative bacterial isolates from HIV patients in South India was analyzed. METHODS: A total of 173 Gram-negative bacterial (GNB) isolates from HIV patients were screened for antibiotic susceptibility profile using the Kirby-Bauer diskdiffusion method. Positivity of drug-resistant genes was analyzed using polymerase chain reaction method. RESULTS: In this study, 72.8% of bacterial isolates were obtained from urine specimens, and Escherichia coli (47.4%) was the predominantly isolated bacterium. Overall, 87.3% and 83.2% of GNB were resistant to 3rd generation cephalosporin antibiotics such as cefotaxime and ceftazidime, respectively, 56.6% were resistant to cephamycin (cefoxitin) and 43% to carbapenem (imipenem) antibiotics. Extended-spectrum ß-lactamases (ESBL) production was noted among 79.5% of GNB isolates, followed by AmpC (57.1%) and Metallo ß-lactamases (37.3%). Molecular analysis revealed that ESBL genes such as blaTEM (94.1%), blaCTX-M (89.2%), and blaSHV (24.2%) were detected at higher levels among GNB isolates. Carbapenemase-producing genes such as blaOXA-48 (20%), blaOXA-23 (2.6%), and both blaOXA-23 and blaOXA-51 like genes (2.6%) and AmpC producing genes such as blaCIT (26.7%), blaDHA (3.6%), and blaACC (1.8%) were detected at low-level. CONCLUSIONS: This study concludes that ESBL producing genes are detected at high level among gram-negative bacterial isolates from HIV patients in South India.

Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine against main protease and RNA-dependent RNA polymerase of SARS-CoV-2: A molecular docking and drug repurposing approach.

BACKGROUND: Outbreak of COVID-19 has been recognized as a global health concern since it causes high rates of morbidity and mortality. No specific antiviral drugs are available for the treatment of COVID-19 till date. Drug repurposing strategy helps to find out the drugs for COVID-19 treatment from existing FDA approved antiviral drugs. In this study, FDA approved small molecule antiviral drugs were repurposed against the major viral proteins of SARS-CoV-2. METHODS: The 3D structures of FDA approved small molecule antiviral drugs were retrieved from PubChem. Virtual screening was performed to find out the lead antiviral drug molecules against main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) using COVID-19 Docking Server. Furthermore, lead molecules were individually docked against protein targets using AutoDock 4.0.1 software and their drug-likeness and ADMET properties were evaluated. RESULTS: Out of 65 FDA approved small molecule antiviral drugs screened, Raltegravir showed highest interaction energy value of -9 kcal/mol against Mpro of SARS-CoV-2 and Indinavir, Tipranavir, and Pibrentasvir exhibited a binding energy value of ≥-8 kcal/mol. Similarly Indinavir showed the highest binding energy of -11.5 kcal/mol against the target protein RdRp and Dolutegravir, Elbasvir, Tipranavir, Taltegravir, Grazoprevir, Daclatasvir, Glecaprevir, Ledipasvir, Pibrentasvir and Velpatasvir showed a binding energy value in range from -8 to -11.2 kcal/mol. The antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine also exhibited good bioavailability and drug-likeness properties. CONCLUSION: This study suggests that the screened small molecule antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine could serve as potential drugs for the treatment of COVID-19 with further validation studies.

Changing drug resistance profile in Pseudomonas aeruginosa infection among HIV patients from 2010-2017: A retrospective study.

OBJECTIVES: Pseudomonas aeruginosa is an important aetiological agent causing pneumonia, urinary tract infections and bacteraemia. High antibiotic use in nosocomial settings and for immunocompromised conditions results in increasing multidrug resistance. This study analysed the antimicrobial resistance profile of P. aeruginosa isolates in an HIV setting. METHODS: A total of 7386 clinical specimens were collected from HIV patients attending YRG CARE from 2010-2017. P. aeruginosa isolated from clinical specimens were identified conventionally, and antimicrobial susceptibility testing was performed by the Kirby-Bauer disk diffusion method. RESULTS: A total of 260 P. aeruginosa strains were isolated, with 165 P. aeruginosa (63.5%) being isolated from hospitalised patients. A higher incidence of P. aeruginosa infection (25.8%) was observed in 2017, and most of the P. aeruginosa were isolated from sputum specimens (57.3%). A high level of resistance was noted to ceftazidime (49.6%), followed by ticarcillin (41.5%). Imipenem and meropenem resistance was observed in 15.0% and 16.9% of P. aeruginosa isolates, respectively. A high rate of imipenem resistance was noted in 2016 (46.2%) and a high rate of meropenem resistance was noted in 2017 (20.5%). An increasing resistance rate of P. aeruginosa was observed against aztreonam, cefepime, levofloxacin, meropenem, piperacillin, piperacillin/tazobactam, ticarcillin and tobramycin from 2010 to 2017. CONCLUSION: A constant increase in drug-resistant P. aeruginosa isolates from HIV patients was observed from 2010 to 2017. Findings from this study urge the need for periodical monitoring and surveillance of the P. aeruginosa resistance profile, especially in hospitalised and immunocompromised patients in resource-limited settings.