Emergence of high colistin resistance in carbapenem resistant Acinetobacter baumannii in Pakistan and its potential management through immunomodulatory effect of an extract from Saussurea lappa.

Carbapenem resistant Acinetobacter baumannii has emerged as one of the most difficult to treat nosocomial bacterial infections in recent years. It was one of the major causes of secondary infections in Covid-19 patients in developing countries. The polycationic polypeptide antibiotic colistin is used as a last resort drug to treat carbapenem resistant A. baumannii infections. Therefore, resistance to colistin is considered as a serious medical threat. The purpose of this study was to assess the current status of colistin resistance in Pakistan, a country where carbapenem resistant A. bumannii infections are endemic, to understand the impact of colistin resistance on virulence in mice and to assess alternative strategies to treat such infections. Out of 150 isolates collected from five hospitals in Pakistan during 2019-20, 84% were carbapenem resistant and 7.3% were additionally resistant to colistin. There were two isolates resistant to all tested antibiotics and 83% of colistin resistant isolates were susceptible to only tetracycline family drugs doxycycline and minocycline. Doxycycline exhibited a synergetic bactericidal effect with colistin even in colistin resistant isolates. Exposure of A. baumannii 17978 to sub inhibitory concentrations of colistin identified novel point mutations associated with colistin resistance. Colistin tolerance acquired independent of mutations in lpxA, lpxB, lpxC, lpxD, and pmrAB supressed the proinflammatory immune response in epithelial cells and the virulence in a mouse infection model. Moreover, the oral administration of water extract of Saussuria lappa, although not showing antimicrobial activity against A. baumannii in vitro, lowered the number of colonizing bacteria in liver, spleen and lung of the mouse model and also lowered the levels of neutrophils and interleukin 8 in mice. Our findings suggest that the S. lappa extract exhibits an immunomodulatory effect with potential to reduce and cure systemic infections by both opaque and translucent colony variants of A. baumannii.

Emergence of high colistin resistance in carbapenem resistant Acinetobacter baumannii in Pakistan and its potential management through immunomodulatory effect of an extract from Saussurea lappa

Carbapenem resistant Acinetobacter baumannii has emerged as one of the most difficult to treat nosocomial bacterial infections in recent years. It was one of the major causes of secondary infections in Covid-19 patients in developing countries. The polycationic polypeptide antibiotic colistin is used as a last resort drug to treat carbapenem resistant A. baumannii infections. Therefore, resistance to colistin is considered as a serious medical threat. The purpose of this study was to assess the current status of colistin resistance in Pakistan, a country where carbapenem resistant A. bumannii infections are endemic, to understand the impact of colistin resistance on virulence in mice and to assess alternative strategies to treat such infections. Out of 150 isolates collected from five hospitals in Pakistan during 2019–20, 84% were carbapenem resistant and 7.3% were additionally resistant to colistin. There were two isolates resistant to all tested antibiotics and 83% of colistin resistant isolates were susceptible to only tetracycline family drugs doxycycline and minocycline. Doxycycline exhibited a synergetic bactericidal effect with colistin even in colistin resistant isolates. Exposure of A. baumannii 17978 to sub inhibitory concentrations of colistin identified novel point mutations associated with colistin resistance. Colistin tolerance acquired independent of mutations in lpxA, lpxB, lpxC, lpxD, and pmrAB supressed the proinflammatory immune response in epithelial cells and the virulence in a mouse infection model. Moreover, the oral administration of water extract of Saussuria lappa, although not showing antimicrobial activity against A. baumannii in vitro, lowered the number of colonizing bacteria in liver, spleen and lung of the mouse model and also lowered the levels of neutrophils and interleukin 8 in mice. Our findings suggest that the S. lappa extract exhibits an immunomodulatory effect with potential to reduce and cure systemic infections by both opaque and translucent colony variants of A. baumannii.

Indian agriculture sector: impacts from COVID-19

The livelihood of around 70% of the Indian rural population depends on the agriculture sector. In India, even the earnings of the non-agriculture sectors in terms of backward and forward linkage for agro-based businesses also get impacted by the production of agricultural products. However, issues like cereal-centric, regionally-biased, and resource-intensive production are still about the agriculture sector of India. The present study attempts to provide an insight into the present scenario of the Indian agriculture sector after providing a brief review of the agricultural literature. Through empirical analysis using multiple regression technique, it tries to find out the factors responsible for the growth of the Indian agriculture sector. The study also explores the potential impact of COVID-19 on the agriculture sector of India based on various secondary sources. The result shows that agriculture trade, level of rainfall, and infrastructure development is significantly and positively, while life expectancy and employment in agriculture are significantly and negatively impacting the agricultural contribution to the GDP of India.

Correction: Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro.

[This corrects the article DOI: 10.1039/D0RA06038K.].

Bacterial Coinfections Increase Mortality of Severely Ill COVID-19 Patients in Saudi Arabia.

Coronavirus disease 19 (COVID-19) is an ongoing global pandemic that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severity and mortality rates of COVID-19 are affected by several factors, such as respiratory diseases, diabetes, and hypertension. Bacterial coinfections are another factor that could contribute to the severity of COVID-19. Limited studies have investigated morbidity and mortality due to microbial coinfections in COVID-19 patients. Here, we retrospectively studied the effects of bacterial coinfections on intensive care unit (ICU)-admitted patients with COVID-19 in Asir province, Saudi Arabia. We analyzed electronic medical records of hospitalized patients with COVID-19 at Asir Central Hospital. A total of 34 patients were included, and the clinical data of 16 patients infected with SARS-CoV-2 only and 18 patients coinfected with SARS-CoV-2 and bacterial infections were analyzed in our study. Our data showed that the length of stay at the hospital for patients infected with both SARS-CoV-2 and bacterial infection was 35.2 days, compared to 16.2 days for patients infected with only SARS-CoV-2 (p = 0.0001). In addition, higher mortality rates were associated with patients in the coinfection group compared to the SARS-CoV-2-only infected group (50% vs. 18.7%, respectively). The study also showed that gram-negative bacteria are the most commonly isolated bacteria in COVID-19 patients. To conclude, this study found that individuals with COVID-19 who presented with bacterial infections are at higher risk for a longer stay at the hospital and potentially death. Further studies with a larger population are warranted to better understand the clinical outcomes of COVID-19 with bacterial infections.

Pharmacological Efficacy and Safety of Glycyrrhiza glabra in the Treatment of Respiratory Tract Infections.

Respiratory tract infections are underestimated because they are mild and disabling, but in clinical medicine, these are the most prevalent problems. According to the World Health Organization third-most comprehensive cause of death in the world till 2030 would be Chronic Obstructive Pulmonary Disease (COPD). Dominating viruses of respiratory infections are influenza, respiratory syncytial virus, rhinoviruses, and human coronaviruses. Antibiotics are mostly used to treat bacterial infections, and they do not effectively manage viral infections like sinusitis, sore throats, bronchitis, influenza, and common respiratory infections. Presently no medication is available only symptomatic interventions is an option in our hand. However, a lot of research is going on the vaccine and drugs-based approaches against respiratory viruses worldwide. Traditional medicines are getting the attraction to treat many diseases. It is vital to screen the medicinal plants to find the potential of new compounds for treatment against antiviral and antimicrobial activities. Glycyrrhiza glabra L. (Licorice) pharmacological actions modulate the immune system, inhibit virus growth, produce anti-inflammatory activity, and inactivate viruses. This comprehensive review mainly focuses on the role of licorice in managing respiratory infections caused by viruses and bacteria, including complications associated with its excess intake. There has been limited human research's exhibited licorice effectiveness in respiratory infections; therefore, there is a need for uncompromising and long-term research. This paper will be a valuable reference for biologists and physicians looking for a medication for respiratory infections. Glycyrrhiza glabra could open the door to novel agents in drug discovery and development.

Efficacy of Dexamethasone for the Treatment of COVID-19 Infection: A Perspective Review.

The current COVID-19 pandemic has provoked the urgent requirement to search for effective treatments since the implications are so huge globally as compared to the earlier pandemics. Momentarily, there has been no effective medicine for SARS-CoV-2 infection, and supportive care tends to be the most effective approach to treat COVID-19 patients. The rapidly growing awareness of SARS-CoV-2 virology offers a large number of possible drug targets. The World Health Organisation (WHO) is steadily updating the treatment protocol for COVID-19 based on the recent clinical trials. In the present review, we have summarised the possible mode of action, clinical evidence, consequences of dexamethasone as the therapeutic agent against Covid-19. Currently, many corticosteroids are being tested in ongoing randomised trials. Dexamethasone could come as the life-saving drug. Dexamethasone drug looks useful only in those patients who are already in a critical state. We might allow dexamethasone as a fascinating shot, if the drug proves to be clinically favourable for long-term health effects of Covid-19 recovered patients. It is commonly accepted to reinforce approved drugs in the fight against newly emerging diseases such as COVID-19 as these drugs have established pharmacokinetic profiles and protection. The current focus should be on the development of novel proven therapeutics along with vaccines. There is a need for high quality, more extensive, rapid and collaborative randomized controlled trials with more control groups.

COVID-19 and SARS-CoV-2 Variants: Current Challenges and Health Concern.

The ongoing coronavirus disease 2019 (COVID-19) outbreak in Wuhan, China, was triggered and unfolded quickly throughout the globe by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The new virus, transmitted primarily through inhalation or contact with infected droplets, seems very contagious and pathogenic, with an incubation period varying from 2 to 14 days. The epidemic is an ongoing public health problem that challenges the present global health system. A worldwide social and economic stress has been observed. The transitional source of origin and its transport to humans is unknown, but speedy human transportation has been accepted extensively. The typical clinical symptoms of COVID-19 are almost like colds. With case fatality rates varying from 2 to 3 percent, a small number of patients may experience serious health problems or even die. To date, there is a limited number of antiviral agents or vaccines for the treatment of COVID-19. The occurrence and pathogenicity of COVID-19 infection are outlined and comparatively analyzed, given the outbreak's urgency. The recent developments in diagnostics, treatment, and marketed vaccine are discussed to deal with this viral outbreak. Now the scientist is concerned about the appearance of several variants over the globe and the efficacy of the vaccine against these variants. There is a need for consistent monitoring of the virus epidemiology and surveillance of the ongoing variant and related disease severity.

COVID-19 preparedness-a survey among neonatal care providers in low- and middle-income countries.

OBJECTIVE: To evaluate COVID-19 pandemic preparedness, available resources, and guidelines for neonatal care delivery among neonatal health care providers in low- and middle-income countries (LMICs) across all continents. STUDY DESIGN: Cross-sectional, web-based survey administered between May and June, 2020. RESULTS: Of 189 invited participants in 69 LMICs, we received 145 (77%) responses from 58 (84%) countries. The pandemic provides significant challenges to neonatal care, particularly in low-income countries. Respondents noted exacerbations of preexisting shortages in staffing, equipment, and isolation capabilities. In Sub-Saharan Africa, 9/35 (26%) respondents noted increased mortality in non-COVID-19-infected infants. Clinical practices on cord clamping, isolation, and breastfeeding varied widely, often not in line with World Health Organization guidelines. Most respondents noted family access restrictions, and limited shared decision-making. CONCLUSIONS: Many LMICs face an exacerbation of preexisting resource challenges for neonatal care during the pandemic. Variable approaches to care delivery and deviations from guidelines provide opportunities for international collaborative improvement.

Is PF-00835231 a Pan-SARS-CoV-2 Mpro Inhibitor? A Comparative Study.

The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.

Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and Other Coronaviruses: A Genome-wide Comparative Annotation and Analysis.

Novel strain of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) causes mild to severe respiratory illness. The early symptoms may be fever, dry cough, sour throat, and difficulty in breathing which may lead to death in severe cases. Compared to previous outbreaks like SARS-CoV and Middle East Respiratory Syndrome (MERS), SARS-CoV2 disease (COVID-19) outbreak has been much distressing due to its high rate of infection but low infection fatality rate (IFR) with 1.4% around the world. World Health Organization (WHO) has declared (COVID-19) a pandemic on March 11, 2020. In the month of January 2020, the whole genome of SARS-CoV2 was sequenced which made work easy for researchers to develop diagnostic kits and to carry out drug repurposing to effectively alleviate the pandemic situation in the world. Now, it is important to understand why this virus has high rate of infectivity or is there any factor involved at the genome level which actually facilitates this virus infection globally? In this study, we have extensively analyzed the whole genomes of different coronaviruses infecting humans and animals in different geographical locations around the world. The main aim of the study is to identify the similarity and the mutational adaptation of the coronaviruses from different host and geographical locations to the SARS-CoV2 and provide a better strategy to understand the mutational rate for specific target-based drug designing. This study is focused to every annotation in a comparative manner which includes SNPs, repeat analysis with the different categorization of the short-sequence repeats and long-sequence repeats, different UTR's, transcriptional factors, and the predicted matured peptides with the specific length and positions on the genomes. The extensive analysis on SNPs revealed that Wuhan SARS-CoV2 and Indian SARS-CoV2 are having only eight SNPs. Collectively, phylogenetic analysis, repeat analysis, and the polymorphism revealed the genomic conserveness within the SARS-CoV2 and few other coronaviruses with very less mutational chances and the huge distance and mutations from the few other species.

Use of Natural Compounds as a Potential Therapeutic Agent Against COVID-19.

The current 2019-nCoV outbreak is becoming extremely harmful and has affected the whole world. Its control is challenging because there is no effective vaccine or drug available for coronavirus disease. The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), previously named as 2019 novel coronavirus (2019-nCoV), primarily targets the human respiratory system to lung lesions and lethal pneumonia. Natural products have always shown a crucial role in the process of drug development against various diseases. They may serve as leads for further drug development to combat emergent mutants of the coronavirus. In this review, the current status of natural compounds and their derivatives acting against different species of CoV are discussed.

Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro.

Novel coronavirus (CoV) is the primary etiological virus responsible for the pandemic that started in Wuhan in 2019-2020. This viral disease is extremely prevalent and has spread around the world. Preventive steps are restricted social contact and isolation of the sick individual to avoid person-to-person transmission. There is currently no cure available for the disease and the search for novel medications or successful therapeutics is intensive, time-consuming, and laborious. An effective approach in managing this pandemic is to develop therapeutically active drugs by repurposing or repositioning existing drugs or active molecules. In this work, we developed a feature-based pharmacophore model using reported compounds that inhibit SARS-CoV-2. This model was validated and used to screen the library of 565 FDA-approved drugs against the viral main protease (Mpro), resulting in 66 drugs interacting with Mpro with higher binding scores in docking experiments than drugs previously reported for the target diseases. The study identified drugs from many important classes, viz. D2 receptor antagonist, HMG-CoA inhibitors, HIV reverse transcriptase and protease inhibitors, anticancer agents and folate inhibitors, which can potentially interact with and inhibit the SARS-CoV-2 Mpro. This validated approach may help in finding the urgently needed drugs for the SARS-CoV-2 pandemic with infinitesimal chances of failure.

Comparative genome analysis of novel coronavirus (SARS-CoV-2) from different geographical locations and the effect of mutations on major target proteins: An in silico insight.

A novel severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) causing COVID-19 pandemic in humans, recently emerged and has exported in more than 200 countries as a result of rapid spread. In this study, we have made an attempt to investigate the SARS-CoV-2 genome reported from 13 different countries, identification of mutations in major coronavirus proteins of these different SARS-CoV-2 genomes and compared with SARS-CoV. These thirteen complete genome sequences of SARS-CoV-2 showed high identity (>99%) to each other, while they shared 82% identity with SARS-CoV. Here, we performed a very systematic mutational analysis of SARS-CoV-2 genomes from different geographical locations, which enabled us to identify numerous unique features of this viral genome. This includes several important country-specific unique mutations in the major proteins of SARS-CoV-2 namely, replicase polyprotein, spike glycoprotein, envelope protein and nucleocapsid protein. Indian strain showed mutation in spike glycoprotein at R408I and in replicase polyprotein at I671T, P2144S and A2798V,. While the spike protein of Spain & South Korea carried F797C and S221W mutation, respectively. Likewise, several important country specific mutations were analyzed. The effect of mutations of these major proteins were also investigated using various in silico approaches. Main protease (Mpro), the therapeutic target protein of SARS with maximum reported inhibitors, was thoroughly investigated and the effect of mutation on the binding affinity and structural dynamics of Mpro was studied. It was found that the R60C mutation in Mpro affects the protein dynamics, thereby, affecting the binding of inhibitor within its active site. The implications of mutation on structural characteristics were determined. The information provided in this manuscript holds great potential in further scientific research towards the design of potential vaccine candidates/small molecular inhibitor against COVID19.