Structure-based screening of natural product libraries in search of potential antiviral drug-leads as first-line treatment to COVID-19 infection.

The study focuses on identifying and screening natural products (NPs) based on their structural similarities with chemical drugs followed by their possible use in first-line treatment to COVID-19 infection. In the present study, the in-house natural product libraries, consisting of 26,311 structures, were screened against potential targets of SARS-CoV-2 based on their structural similarities with the prescribed chemical drugs. The comparison was based on molecular properties, 2 and 3-dimensional structural similarities, activity cliffs, and core fragments of NPs with chemical drugs. The screened NPs were evaluated for their therapeutic effects based on their predicted in-silico pharmacokinetic and pharmacodynamics properties, binding interactions with the appropriate targets, and structural stability of the bound complex using molecular dynamics simulations. The study yielded NPs with significant structural similarities to synthetic drugs currently used to treat COVID-19 infections. The study proposes the probable biological action of the selected NPs as Anti-retroviral protease inhibitors, RNA-dependent RNA polymerase inhibitors, and viral entry inhibitors.

Impact of the COVID-19 pandemic on the surveillance, prevention and control of antimicrobial resistance: a global survey.

OBJECTIVES: The COVID-19 pandemic has had a substantial impact on health systems. The WHO Antimicrobial Resistance (AMR) Surveillance and Quality Assessment Collaborating Centres Network conducted a survey to assess the effects of COVID-19 on AMR surveillance, prevention and control. METHODS: From October to December 2020, WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) national focal points completed a questionnaire, including Likert scales and open-ended questions. Data were descriptively analysed, income/regional differences were assessed and free-text questions were thematically analysed. RESULTS: Seventy-three countries across income levels participated. During the COVID-19 pandemic, 67% reported limited ability to work with AMR partnerships; decreases in funding were frequently reported by low- and middle-income countries (LMICs; P < 0.01). Reduced availability of nursing, medical and public health staff for AMR was reported by 71%, 69% and 64%, respectively, whereas 67% reported stable cleaning staff availability. The majority (58%) reported reduced reagents/consumables, particularly LMICs (P < 0.01). Decreased numbers of cultures, elective procedures, chronically ill admissions and outpatients and increased ICU admissions reported could bias AMR data. Reported overall infection prevention and control (IPC) improvement could decrease AMR rates, whereas increases in selected inappropriate IPC practices and antimicrobial prescribing could increase rates. Most did not yet have complete data on changing AMR rates due to COVID-19. CONCLUSIONS: This was the first survey to explore the global impact of COVID-19 on AMR among GLASS countries. Responses highlight important actions to help ensure that AMR remains a global health priority, including engaging with GLASS to facilitate reliable AMR surveillance data, seizing the opportunity to develop more sustainable IPC programmes, promoting integrated antibiotic stewardship guidance, leveraging increased laboratory capabilities and other system-strengthening efforts.

Evolutionary selectivity of amino acid is inspired from the enhanced structural stability and flexibility of the folded protein.

AIM: The present study attempts to decipher the site-specific amino acid alterations at certain positions experiencing preferential selectivity and their effect on proteins' stability and flexibility. The study examines the selection preferences by considering pair-wise non-bonded interaction energies of adjacent and interacting amino acids present at the interacting site, along with their evolutionary history. MATERIALS AND METHODS: For the study, variations in the interacting residues of spike protein (S-Protein) receptor-binding domain (RBD) of different coronaviruses were examined. The MD simulation trajectory analysis revealed that, though all the variants studied were structurally stable at their native and bound confirmations, the RBD of 2019-nCoV/SARS-CoV-2 was found to be more flexible and more dynamic. Furthermore, a noticeable change observed in the non-bonded interaction energies of the amino acids interacting with the receptor corroborated their selection at respective positions. KEY FINDINGS: The conformational changes exerted by the altered amino acids could be the reason for a broader range of interacting receptors among the selected proteins. SIGNIFICANCE: The results envisage a strong indication that the residue selection at certain positions is governed by a well-orchestrated feedback mechanism, which follows increased stability and flexibility in the folded structure compared to its evolutionary predecessor.

Infection and transmission of SARS-CoV-2 in London care homes reporting no cases or outbreaks of COVID-19: Prospective observational cohort study, England 2020.

BACKGROUND: Care homes have been disproportionately affected by the COVID-19 pandemic. We investigated the potential role of asymptomatic infection and silent transmission in London care homes that reported no cases of COVID-19 during the first wave of the pandemic. METHODS: Five care homes with no cases and two care homes reporting a single case of COVID-19 (non-outbreak homes) were investigated with nasal swabbing for SARS-CoV-2 RT-PCR and serology for SARS-CoV-2 antibodies five weeks later. Whole genome sequencing (WGS) was performed on RT-PCR positive samples. Serology results were compared with those of six care homes with recognised outbreaks. FINDINGS: Across seven non-outbreak homes, 718 (387 staff, 331 residents) individuals had a nasal swab and 651 (386 staff, 265 residents) had follow-up serology. Sixteen individuals (13 residents, 3 staff) in five care homes with no reported cases were RT-PCR positive (care home positivity rates, 0 to 7.6%) compared to 13 individuals (3.0 and 10.8% positivity) in two homes reporting a single case.Seropositivity across these seven homes varied between 10.7-56.5%, with four exceeding community seroprevalence in London (14.8%). Seropositivity rates for staff and residents correlated significantly (rs 0.84, [95% CI 0.51-0.95] p <0.001) across the 13 homes. WGS identified multiple introductions into some homes and silent transmission of a single lineage between staff and residents in one home. INTERPRETATION: We found high rates of asymptomatic infection and transmission even in care homes with no COVID-19 cases. The higher seropositivity rates compared to RT-PCR positivity highlights the true extent of the silent outbreak. FUNDING: PHE.

Mass testing after a single suspected or confirmed case of COVID-19 in London care homes, April-May 2020: implications for policy and practice.

INTRODUCTION: Previous investigations have identified high rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among residents and staff in care homes reporting an outbreak of coronavirus disease 2019 (COVID-19). We investigated care homes reporting a single suspected or confirmed case to assess whether early mass testing might reduce risk of transmission during the peak of the pandemic in London. METHODS: Between 18 and 27 April 2020, residents and staff in care homes reporting a single case of COVID-19 to Public Health England had a nasal swab to test for SARS-CoV-2 infection by reverse transcription polymerase chain reaction and subsequent whole-genome sequencing. Residents and staff in two care homes were re-tested 8 days later. RESULTS: Four care homes were investigated. SARS-CoV-2 positivity was 20% (65/333) overall, ranging between 3 and 59%. Among residents, positivity ranged between 3 and 76% compared with 3 and 40% in staff. Half of the SARS-CoV-2-positive residents (23/46, 50%) and 63% of staff (12/19) reported symptoms within 14 days before or after testing. Repeat testing 8 days later in two care homes with the highest infection rates identified only two new cases. Genomic analysis demonstrated a small number of introduction of the virus into care homes, and distinct clusters within three of the care homes. CONCLUSIONS: We found extensive but variable rates of SARS-CoV-2 infection among residents and staff in care homes reporting a single case of COVID-19. Although routine whole-home testing has now been adopted into practice, care homes must remain vigilant and should be encouraged to report a single suspected case, which should trigger appropriate outbreak control measures.

High prevalence of SARS-CoV-2 antibodies in care homes affected by COVID-19: Prospective cohort study, England.

BACKGROUND: We investigated six London care homes experiencing a COVID-19 outbreak and found high rates of SARS-CoV-2 infection among residents and staff. Here we report follow-up investigations including antibody testing in the same care homes five weeks later. METHODS: Residents and staff in the initial investigation had a repeat nasal swab for SARS-CoV-2 RT-PCR and a blood test for SARS CoV-2 antibodies using ELISA based on SARS-CoV-2 native viral antigens derived from infected cells and virus neutralisation. FINDINGS: Of the 518 residents and staff in the initial investigation, 186/241 (77.2%) surviving residents and 208/254 (81.9%) staff underwent serological testing. Almost all SARS-CoV-2 RT-PCR positive residents and staff were seropositive five weeks later, whether symptomatic (residents 35/35, 100%; staff, 22/22, 100%) or asymptomatic (residents 32/33, 97.0%; staff 21/22, 95.5%). Symptomatic but SARS-CoV-2 RT-PCR negative residents and staff also had high seropositivity rates (residents 23/27, 85.2%; staff 18/21, 85.7%), as did asymptomatic RT-PCR negative individuals (residents 61/91, 67.0%; staff 95/143, 66.4%). Neutralising antibody was detected in 118/132 (89.4%) seropositive individuals and was not associated with age or symptoms. Ten residents (10/79 re-tested, 12.7%) remained RT-PCR positive but with higher RT-PCR cycle threshold values; 7/10 had serological testing and all were seropositive. New infections were detected in three residents and one staff. INTERPRETATION: RT-PCR provides a point prevalence of SARS-CoV-2 infection but significantly underestimates total exposure in outbreak settings. In care homes experiencing large COVID-19 outbreaks, most residents and staff had neutralising SARS-CoV-2 antibodies, which was not associated with age or symptoms. FUNDING: PHE.

Increased risk of SARS-CoV-2 infection in staff working across different care homes: enhanced CoVID-19 outbreak investigations in London care Homes.

BACKGROUND: Care homes have been disproportionately affected by the COVID-19 pandemic and continue to suffer large outbreaks even when community infection rates are declining, thus representing important pockets of transmission. We assessed occupational risk factors for SARS-CoV-2 infection among staff in six care homes experiencing a COVID-19 outbreak during the peak of the pandemic in London, England. METHODS: Care home staff were tested for SARS-COV-2 infection by RT-PCR and asked to report any symptoms, their contact with residents and if they worked in different care homes. Whole genome sequencing (WGS) was performed on RT-PCR positive samples. RESULTS: In total, 53 (21%) of 254 staff were SARS-CoV-2 positive but only 12/53 (23%) were symptomatic. Among staff working in a single care home, SARS-CoV-2 positivity was 15% (2/13), 16% (7/45) and 18% (30/169) in those reporting no, occasional and regular contact with residents. In contrast, staff working across different care homes (14/27, 52%) had a 3.0-fold (95% CI, 1.9-4.8; P<0.001) higher risk of SARS-CoV-2 positivity than staff working in single care homes (39/227, 17%). WGS identified SARS-CoV-2 clusters involving staff only, including some that included staff working across different care homes. CONCLUSIONS: SARS-CoV-2 positivity was significantly higher among staff working across different care homes than those who were working in the same care home. We found local clusters of SARS-CoV-2 infection between staff only, including those with minimal resident contact. Infection control should be extended for all contact, including those between staff, whilst on care home premises.

Investigation of SARS-CoV-2 outbreaks in six care homes in London, April 2020.

BACKGROUND: Care homes are experiencing large outbreaks of COVID-19 associated with high case-fatality rates. We conducted detailed investigations in six London care homes reporting suspected COVID-19 outbreaks during April 2020. METHODS: Residents and staff had nasal swabs for SARS CoV-2 testing using RT-PCR and were followed-up for 14 days. They were categorized as symptomatic, post-symptomatic or pre-symptomatic if they had symptoms at the time of testing, in the two weeks before or two weeks after testing, respectively, or asymptomatic throughout. Virus isolation and whole genome sequencing (WGS) was also performed. FINDINGS: Across the six care homes, 105/264 (39.8%) residents were SARS CoV-2 positive, including 28 (26.7%) symptomatic, 10 (9.5%) post-symptomatic, 21 (20.0%) pre-symptomatic and 46 (43.8%) who remained asymptomatic. Case-fatality at 14-day follow-up was highest among symptomatic SARS-CoV-2 positive residents (10/28, 35.7%) compared to asymptomatic (2/46, 4.3%), post-symptomatic (2/10, 20.0%) or pre-symptomatic (3/21,14.3%) residents. Among staff, 53/254 (20.9%) were SARS-CoV-2 positive and 26/53 (49.1%) remained asymptomatic. RT-PCR cycle-thresholds and live-virus recovery were similar between symptomatic/asymptomatic residents/staff. Higher RT-PCR cycle threshold values (lower virus load) samples were associated with exponentially decreasing ability to recover infectious virus (P<0.001). WGS identified multiple (up to 9) separate introductions of different SARS-CoV-2 strains into individual care homes. INTERPRETATION: A high prevalence of SARS-CoV-2 positivity was found in care homes residents and staff, half of whom were asymptomatic and potential reservoirs for on-going transmission. A third of symptomatic SARS-CoV-2 residents died within 14 days. Symptom-based screening alone is not sufficient for outbreak control. FUNDING: None.