Exploration of Streptococcus core genome to reveal druggable targets and novel therapeutics against S. pneumoniae.

Streptococcus pneumoniae (S. pneumoniae), the major etiological agent of community-acquired pneumonia (CAP) contributes significantly to the global burden of infectious diseases which is getting resistant day by day. Nearly 30% of the S. pneumoniae genomes encode hypothetical proteins (HPs), and better understandings of these HPs in virulence and pathogenicity plausibly decipher new treatments. Some of the HPs are present across many Streptococcus species, systematic assessment of these unexplored HPs will disclose prospective drug targets. In this study, through a stringent bioinformatics analysis of the core genome and proteome of S. pneumoniae PCS8235, we identified and analyzed 28 HPs that are common in many Streptococcus species and might have a potential role in the virulence or pathogenesis of the bacteria. Functional annotations of the proteins were conducted based on the physicochemical properties, subcellular localization, virulence prediction, protein-protein interactions, and identification of essential genes, to find potentially druggable proteins among 28 HPs. The majority of the HPs are involved in bacterial transcription and translation. Besides, some of them were homologs of enzymes, binding proteins, transporters, and regulators. Protein-protein interactions revealed HP PCS8235_RS05845 made the highest interactions with other HPs and also has TRP structural motif along with virulent and pathogenic properties indicating it has critical cellular functions and might go under unconventional protein secretions. The second highest interacting protein HP PCS8235_RS02595 interacts with the Regulator of chromosomal segregation (RocS) which participates in chromosome segregation and nucleoid protection in S. pneumoniae. In this interacting network, 54% of protein members have virulent properties and 40% contain pathogenic properties. Among them, most of these proteins circulate in the cytoplasmic area and have hydrophilic properties. Finally, molecular docking and dynamics simulation demonstrated that the antimalarial drug Artenimol can act as a drug repurposing candidate against HP PCS8235_RS 04650 of S. pneumoniae. Hence, the present study could aid in drugs against S. pneumoniae.

Impact of community masking on COVID-19: A cluster-randomized trial in Bangladesh.

We conducted a cluster-randomized trial to measure the effect of community-level mask distribution and promotion on symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in rural Bangladesh from November 2020 to April 2021 (N = 600 villages, N = 342,183 adults). We cross-randomized mask type (cloth versus surgical) and promotion strategies at the village and household level. Proper mask-wearing increased from 13.3% in the control group to 42.3% in the intervention arm (adjusted percentage point difference = 0.29; 95% confidence interval = [0.26, 0.31]). The intervention reduced symptomatic seroprevalence (adjusted prevalence ratio = 0.91 [0.82, 1.00]), especially among adults ≥60 years old in villages where surgical masks were distributed (adjusted prevalence ratio = 0.65 [0.45, 0.85]). Mask distribution with promotion was a scalable and effective method to reduce symptomatic SARS-CoV-2 infections.

Microsecond molecular dynamics simulations revealed the inhibitory potency of amiloride analogs against SARS-CoV-2 E viroporin.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes small envelope protein (E) that plays a major role in viral assembly, release, pathogenesis, and host inflammation. Previous studies demonstrated that pyrazine ring containing amiloride analogs inhibit this protein in different types of coronavirus including SARS-CoV-1 small envelope protein E (SARS-CoV-1 E). SARS-CoV-1 E has 93.42% sequence identity with SARS-CoV-2 E and shared a conserved domain NS3/small envelope protein (NS3_envE). Amiloride analog hexamethylene amiloride (HMA) can inhibit SARS-CoV-1 E. Therefore, we performed molecular docking and dynamics simulations to explore whether amiloride analogs are effective in inhibiting SARS-CoV-2 E. To do so, SARS-CoV-1 E and SARS-CoV-2 E proteins were taken as receptors while HMA and 3-amino-5-(azepan-1-yl)-N-(diaminomethylidene)-6-pyrimidin-5-ylpyrazine-2-carboxamide (3A5NP2C) were selected as ligands. Molecular docking simulation showed higher binding affinity scores of HMA and 3A5NP2C for SARS-CoV-2 E than SARS-CoV-1 E. Moreover, HMA and 3A5NP2C engaged more amino acids in SARS-CoV-2 E. Molecular dynamics simulation for 1 µs (1,000 ns) revealed that these ligands could alter the native structure of the proteins and their flexibility. Our study suggests that suitable amiloride analogs might yield a prospective drug against coronavirus disease 2019.