Changing Landscape of Antimicrobial Resistance in Neonatal Sepsis: An in silico Analyses of Multidrug Resistance in Klebsiella pneumoniae.

BACKGROUND: Neonatal sepsis poses a critical healthcare concern, as multidrug-resistant Klebsiella pneumoniae (K. pneumoniae) infections are on the rise. Understanding the antimicrobial susceptibility patterns and underlying resistance mechanism is crucial for effective treatment. OBJECTIVES: This study aimed to comprehensively investigate the antimicrobial susceptibility patterns of K. pneumoniae strains responsible for neonatal sepsis using in silico tools. We sought to identify trends and explore reasons for varying resistance levels, particularly for ß-lactams and fluoroquinolone. METHODS: K. pneumoniae isolated from neonates at Kanchi Kamakoti CHILDS Trust Hospital (2017-2020) were analyzed for antimicrobial resistance. Elevated resistance to ß-lactam and fluoroquinolone antibiotics was further investigated through molecular docking and interaction analysis. ß-lactam affinity with penicillin-binding proteins and ß-lactamases was examined. Mutations in ParC and GyrA responsible for quinolone resistance were introduced to investigate ciprofloxacin interactions. RESULTS: Of 111 K. pneumoniae blood sepsis isolates in neonates, high resistance was detected to ß-lactams such as cefixime (85.91%, n = 71), ceftriaxone (84.9%, n = 106), cefotaxime (84.9%, n = 82) and fluoroquinolone (ciprofloxacin- 79.44%, n = 107). Molecular docking revealed low ß-lactam binding toward penicillin-binding proteins and higher affinities for ß-lactamases, attributing to the reduced ß-lactam efficiency. Additionally, ciprofloxacin showed decreased affinity toward mutant ParC and GyrA in comparison to their corresponding wild-type proteins. CONCLUSION: Our study elucidates altered resistance profiles in neonatal sepsis caused by K. pneumoniae, highlighting mechanisms of ß-lactam and fluoroquinolone resistance. It underscores the urgent need for the development of sustainable therapeutic alternatives to address the rising antimicrobial resistance in neonatal sepsis.

Whole genome analysis reveals unique traits of SARS-CoV-2 in pediatric patients.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to challenge the global healthcare with emerging variants and higher infectivity as well as morbidities. This study investigated potential age-related variations through genomic characterization of the virus under common clinical settings. A cohort comprising 71 SARS-CoV-2 strains from both infected infants and accompanying adults, diagnosed via RT-PCR at a tertiary pediatric hospital and research center, underwent Illumina paired-end sequencing. The subsequent analysis involved standard genomic screening, phylogeny construction, and mutational analyses. The analyzed SARSCoV- 2 strains were compared with globally circulating variants. The overall distribution revealed 67.61 % Delta, 25.7 % Omicron, and 1 % either Kappa or Alpha variants. In 2021, Delta predominated at âˆ¼ 94 %, with Alpha/Kappa accounting for around 5 %. However, in 2022, over 94 % of the samples were Omicron variants, signifying a substantial shift from Delta dominance. Delta variants constituted 69.5 % of infections in adults and 78.5 % in infants, while Omicron variants were responsible for 31 % of cases in infants and 18 % in adults. The Spike region harbored the majority of mutations, with T19R being the most prevalent mutation in the Delta lineage. Notably, the frequencies of this mutation varied between infants and adults. In Omicron samples, G142D emerged as the most prevalent mutation. Our dataset predominantly featured clade 21A and lineage B.1.617.2. This study underscores the differential clinical presentations and genomic characteristics of SARS-CoV-2 in pediatric patients and accompanying adults. Understanding the dynamic evolution of the SARS- CoV-2 in both pediatric and adults can help in strengthening prophylactic measures.

Computational study of the piperidine and FtsZ interaction in Salmonella Typhi: implications for disrupting cell division machinery.

FtsZ, a bacterial cell division protein, is essential for assembling the contractile Z-ring crucial in bacterial cytokinesis. Consequently, inhibiting FtsZ could impede proto-filaments, disrupting FtsZ and other associated proteins vital for cell division machinery. Conduct an in-silico drug interaction study to identify novel drug candidates that inhibit the FtsZ protein, aiming to prevent Multi-Drug Resistant (MDR) Salmonella Typhi. Data mining was performed based on piperidine compounds, which were subsequently screened for safe pharmacokinetic profiles. Compounds that met favorable drug-likeness criteria underwent virtual screening against the FtsZ drug target. Two compounds were chosen for molecular docking and molecular dynamic simulation to verify the binding affinity and stability between the target protein and the potential compounds. The 400 isoforms of piperidine analogues were curated, among them potent compound ZINC000000005416 found to possess high binding affinity (-8.49 kcal/mol) and low dissociation constant (0.597 µM). The highest binding affinity shown by ZINC000000005416 was validated by hydrogen bonds, hydrophobic interaction, and salt bridges with the functional domain of the cell division regulatory protein. Docking profiles, when correlated with molecular dynamic simulation (MDS) depicted stable trajectories and compatible conformational changes in the FtsZ-ZINC000000005416 complex. The stable simulated trajectories were validated through free-energy calculations using the Molecular Mechanics-Poisson Boltzmann Surface Area (MM/PBSA) module. Low energy conformations, although the simulation trajectory confirmed the stable ZINC000000005416-FtsZ interaction, which encouraged experimental validations. This study encourages further exploration of the compound ZINC000000005416 as a drug candidate inhibiting FtsZ protein against MDR Salmonella Typhi.Communicated by Ramaswamy H. Sarma.

Coinfections in human papillomavirus associated cancers and prophylactic recommendations.

The Human Papillomavirus (HPV) infection is responsible for more than 80% of reported cervical cancer and other virus-associated tumours. Although this global threat can be controlled using effective vaccination strategies, a growing perturbation of HPV infection is an emerging coinfection likely to increase the severity of the infection in humans. Moreover, these coinfections prolong the HPV infections, thereby risking the chances for oncogenic progression. The present review consolidated the clinically significant microbial coinfections/co-presence associated with HPV and their underlying molecular mechanisms. We discussed the gaps and concerns associated with demography, present vaccination strategies, and other prophylactic limitations. We concluded our review by highlighting the potential clinical as well as emerging computational intervention measures to kerb down HPV-associated severities.

Genomic investigation unveils colistin resistance mechanism in carbapenem-resistant Acinetobacter baumannii clinical isolates.

Colistin resistance in Acinetobacter baumannii is mediated by multiple mechanisms. Recently, mutations within pmrABC two-component system and overexpression of eptA gene due to upstream insertion of ISAba1 have been shown to play a major role. Thus, the aim of our study is to characterize colistin resistance mechanisms among the clinical isolates of A. baumannii in India. A total of 207 clinical isolates of A. baumannii collected from 2016 to 2019 were included in this study. Mutations within lipid A biosynthesis and pmrABC genes were characterized by whole-genome shotgun sequencing. Twenty-eight complete genomes were further characterized by hybrid assembly approach to study insertional inactivation of lpx genes and the association of ISAba1-eptA. Several single point mutations (SNPs), like M12I in pmrA, A138T and A444V in pmrB, and E117K in lpxD, were identified. We are the first to report two novel SNPs (T7I and V383I) in the pmrC gene. Among the five colistin-resistant A. baumannii isolates where complete genome was available, the analysis showed that three of the five isolates had ISAba1 insertion upstream of eptA. No mcr genes were identified among the isolates. We mapped the SNPs on the respective protein structures to understand the effect on the protein activity. We found that majority of the SNPs had little effect on the putative protein function; however, some SNPs might destabilize the local structure. Our study highlights the diversity of colistin resistance mechanisms occurring in A. baumannii, and ISAba1-driven eptA overexpression is responsible for colistin resistance among the Indian isolates.IMPORTANCEAcinetobacter baumannii is a Gram-negative, emerging and opportunistic bacterial pathogen that is often associated with a wide range of nosocomial infections. The treatment of these infections is hindered by increase in the occurrence of A. baumannii strains that are resistant to most of the existing antibiotics. The current drug of choice to treat the infection caused by A. baumannii is colistin, but unfortunately, the bacteria started to show resistance to the last-resort antibiotic. The loss of lipopolysaccharides and mutations in lipid A biosynthesis genes are the main reasons for the colistin resistance. The present study characterized 207 A. baumannii clinical isolates and constructed complete genomes of 28 isolates to recognize the mechanisms of colistin resistance. We showed the mutations in the colistin-resistant variants within genes essential for lipid A biosynthesis and that cause these isolates to lose the ability to produce lipopolysaccharides.

Novel Antimicrobial Peptide SAAP Mutant as a Better Adjuvant to Sulbactam-Based Treatments Against Clinical Strains of XDR Acinetobacter baumannii.

The production of extended spectrum ß-lactamases (ESBLs) in extensively drug-resistant (XDR) strains of Acinetobacter baumannii has created havoc amongst clinicians making the treatment procedure challenging. Carbapenem-resistant strains have displayed total ineffectiveness towards newer combinations of ß-lactam-ß-lactamase inhibitors (ßL-ßLI) in tertiary healthcare settings. Therefore, the present study was aimed to design potential ß-lactamase antimicrobial peptide (AMP) inhibitors against ESBLs produced by the strains. We have constructed an AMP mutant library with higher antimicrobial efficacy (range: ~ 15 to 27%) than their parent peptides. The mutants were thoroughly screened based on different physicochemical and immunogenic properties revealing three peptides, namely SAAP-148, HFIAP-1, myticalin-C6 and their mutants with safe pharmacokinetics profile. Molecular docking highlighted SAAP-148_M15 displaying maximum inhibitory potential with lowest binding energies against NDM1 (- 1148.7 kcal/mol), followed by OXA23 (- 1032.5 kcal/mol) and OXA58 (- 925.3 kcal/mol). The intermolecular interaction profiles displayed SAAP-148_M15 exhibiting hydrogen bonds and van der Waals hydrophobic interactions with the crucial residues of metallo ß-lactamase [IPR001279] and penicillin-binding transpeptidase [IPR001460] domains. Coarse-grained clustering and molecular dynamics simulations (MDS) further validated the stable backbone profile and minimal residue-level fluctuations of the protein-peptide complex that were maintained throughout the simulation timeframe. The present study hypothesised that the combination of sulbactam (ßL) with SAAP-148_M15 (ßLI) holds immense potential in inhibiting the ESBLs alongside restoration of sulbactam activity. The current in silico findings upon further experimental validations can pave path towards designing of successful therapeutic strategy against XDR strains of A. baumannii.

Elucidating the molecular role of MUC5B in progressive lung adenocarcinoma: Prospects for early diagnosis.

Gel-forming mucin MUC5B is significantly deregulated in lung adenocarcinoma (LUAD), however, its role in tumor progression is not yet clearly understood. Here, we used an integrated computational-pipeline-initiated with gene expression analysis followed by network, functional-enrichment, O-linked glycosylation analyses, mutational profiling, and immune cell infiltration estimation to functionally characterize MUC5B gene in LUAD. Thereafter, clinical biomarker validation was supported by the overall survival (OA) and comparative expression profiling across clinical stages using computational algorithms. The gene expression profile of LUAD identified MUC5B to be significantly up-regulated (logFC: 2.36; p-value: 0.01). Network analysis on LUAD interactome screened MUC5B-related genes, having key enrichment in immune suppression and O-linked glycosylation with serine-threonine-rich tandem repeats being highly glycosylated. Furthermore, positive correlation of mutant MUC5B with immune cells in tumor microenvironment (TME) such as cancer-associated fibroblasts and myeloid-derived suppressor cells indicates TME-mediated tumor progression. The positive correlation with immune inhibitors suggested the enhanced tumor proliferation mediated by MUC5B. Structural stability due to genetic alterations identified overall rigid N-H-backbone dynamics (S2 : 0.756), indicating an overall stable mutant protein. Moreover, the low median OA (<50 months) with a hazard ratio of 1.4 and clinical profile of MUC5B gene showed high median expression corresponding to lymph node (N2) and tumor (T3) stages. Our study concludes by highlighting the functional role of O-glycosylated and mutant MUC5B in promoting LUAD by immune suppression. Further, clinical gene expression validation of MUC5B suggests its potential role as a diagnostic biomarker for LUAD metastasis.

Consolidated knowledge-guided computational pipeline for therapeutic intervention against bacterial biofilms - a review.

Biofilm-associated bacterial infections attributed to multifactorial antimicrobial resistance have caused worldwide challenges in formulating successful treatment strategies. In search of accelerated yet cost-effective therapeutics, several researchers have opted for bioinformatics-based protocols to systemize targeted therapies against biofilm-producing strains. The present review investigated the up-to-date computational databases and servers dedicated to anti-biofilm research to design/screen novel biofilm inhibitors (antimicrobial peptides/phytocompounds/synthetic compounds) and predict their biofilm-inhibition efficacy. Scrutinizing the contemporary in silico methods, a consolidated approach has been highlighted, referred to as a knowledge-guided computational pipeline for biofilm-targeted therapy. The proposed pipeline has amalgamated prominently employed methodologies in genomics, transcriptomics, interactomics and proteomics to identify potential target proteins and their complementary anti-biofilm compounds for effective functional inhibition of biofilm-linked pathways. This review can pave the way for new portals to formulate successful therapeutic interventions against biofilm-producing pathogens.

Structure Elucidation and Interaction Dynamics of MefA-MsrD Efflux Proteins in Streptococcus pneumoniae: Impact on Macrolide Susceptibility.

Macrolides are empirically used to treat bacterial community-acquired pneumonia (CAP). Streptococcus pneumoniae, being the major pathogen responsible for bacterial CAP with high mortality rates, express MefA-MsrD efflux pumps to hinder macrolide susceptibility. Despite its importance, the structural features of the efflux-protein complex and its impact on macrolide susceptibility have not yet been elucidated explicitly. Therefore, in the present study, combining homology, threading, and dynamics approaches, MefA and MsrD proteins in pathogenic S. pneumoniae were modeled. Both membrane (lipid-bilayer) and cytoplasmic (aqueous) environments were considered to simulate the MefA and MsrD proteins in their ideal cellular conditions followed by dynamics analyses. The simulated MefA structure represented a typical major facilitator superfamily protein structure with 13 transmembrane helices. MefA-MsrD interaction via clustering-based docking revealed low-energy conformers with stable intermolecular interactions. The higher clinical MIC value of azithromycin over erythromycin was reflected upon erythromycin eliciting stronger interactions (dissociation constant or ki = ∼52 µM) with the cytoplasmic ATP-binding MsrD than azithromycin (ki = ∼112 µM). The strong (binding energy = -132.1 ± 9.5 kcal/mol) and highly stable (root-mean-square fluctuation < 1.0 Å) physical association between MefA with MsrD was validated and was found to be unaffected by the antibiotic binding. Higher propensity of the macrolides to interact with MsrD than MefA established the importance of the former in macrolide susceptibility. Ours is probably the first report on the structural arrangements in the MefA-MsrD efflux complex and the macrolide susceptibility in S. pneumoniae. This study provides a novel lead for experimental explorations and efflux-pump inhibitor designs.

Potential Signature Therapeutic Biomarkers TOP2A, MAD2L1, and CDK1 in Colorectal Cancer: A Systems Biomedicine-Based Approach.

Colorectal cancer is the third deadliest and fourth most diagnosed cancer. It is heterogeneously driven by varied mutations and mutagens, and thus, it is challenging for targeted therapy. The rapid advancement of high-throughput technology presents considerable opportunities for discovering new colon cancer biomarkers. In the present study, we have explored and identified the biomarkers based on molecular interactions. We curated cancer datasets that were not micro-dissected and performed gene expression analysis. The protein-protein interactions were curated, and a network was constructed for the up-regulated genes. The hub genes were analyzed using 12 different topological parameters. The correlation analysis selected TOP2A, CDK1, CCNB1, AURKA, and MAD2L1 as hub genes. Further, survival analysis was performed to determine the effectiveness of the hub gene on the patient's survival rate. Our findings explore various transcription factors such as E2F4, FOXM1, E2F6, MAX, and SIN3A, along with kinases CSNK2A1, MAPK14, CDK1, CDK4, and CDK2, as potential molecular signatures and aid researchers in understanding the pathophysiological mechanisms underlying CRC development and thus providing novel therapeutic and diagnostic recourse. Furthermore, investigating miRNAs, we focused on hsa-miR-215-5p, hsa-miR-192-5p, and hsa-miR-193b-3p due to their observed impact on a diverse set of colorectal cancer genes. Thereby, the current approach brings into light CRC- related genes at the RNA and protein levels that can potentially act as novel biomarkers opening doors to diagnostic and treatment purposes.

Pan-genome and reverse vaccinology approaches to design multi-epitope vaccine against Epstein-Barr virus associated with colorectal cancer.

Epstein-Barr virus (EBV) is a global lymphotropic virus and has been associated with various malignancies, among which colorectal cancer (CRC) is the prevalent one causing mortality worldwide. In the recent past, numerous research efforts have been made to develop a potential vaccine against this virus; however, none is effective possibly due to their low throughput, laboriousness, and lack of sensitivity. In this study, we designed a multi-epitope subunit vaccine that targets latent membrane protein (LMP-2B) of EBV using pan-genome and reverse vaccinology approaches. Twenty-three major histocompatibility complex (MHC) epitopes (five class-I and eighteen class-II) and eight B-cell epitopes, which have been found to be antigenic, immunogenic, and non-toxic, were selected for the vaccine construction. Furthermore, 24 vaccine constructs (VCs) were designed from the predicted epitopes and out of which VC1 was selected and finalized based on its structural parameters. The functionality of VC1 was validated through molecular docking with different immune receptors (MHC class-I, MHC class-II, and TLRs). The binding affinity, molecular and immune simulation revealed that the VC1 had more stable interaction and is believed to elicit good immune responses against EBV. HIGHLIGHTS: Pan-genome and reverse vaccinology approaches were used to design a multi-epitope subunit vaccine against LMP-2B protein of EBV. Epitopes were selected based on the antigenic, immunogenic, and non-toxic properties. Twenty-four vaccine constructs (VCs) were designed from the predicted epitopes. Designed vaccine VC1 has shown good binding affinity and molecular and immune simulation. VC1 was validated using molecular docking with different immune receptors.

NFX1-123: A potential therapeutic target in cervical cancer.

NFX1-123 is a splice variant isoform of the NFX1 gene. It is highly expressed in cervical cancers caused by HPV, and NFX1-123 is a protein partner with the HPV oncoprotein E6. Together, NFX1-123 and E6 affect cellular growth, longevity, and differentiation. The expression status of NFX1-123 in cancers beyond cervical and head and neck cancers, and its potential as therapeutic target, have not been investigated. TSVdb of TCGA was used to quantify NFX1-123 expression in 24 cancers compared with normal tissues. The NFX1-123 protein structure was predicted and then submitted to retrieve suitable drug molecules. The top four compounds, found to bind in silico to NFX1-123, were tested experimentally to determine their effects on NFX1-123-related cellular growth, survival, and migration. 46% of cancers (11 of 24 had significant differences in NFX1-123 expression, with nine having had greater NFX1-123 expression, when compared with adjacent normal tissues. Bioinformatics and proteomic predictive analysis modeled the three-dimensional structure of NFX1-123, and drug libraries were screened for high-binding affinity compounds using this modeled structure. Seventeen drugs with binding energies ranging from -1.3 to -10 Kcal/mol were identified. The top four compounds were used to treat HPV- and HPV+ cervical cancer cell lines, three of which (Ropitoin, R428 and Ketoconazole) reduced NFX1-123 protein levels, inhibited cellular growth, survival, and migration, and enhanced the cytotoxicity of Cisplatin. These findings highlight cancers expressing high levels of NFX1-123, and drugs that target it, may reduce cellular growth, survival, and migration, making NFX1-123 a potential novel therapeutic target.

FN1 and cancer-associated fibroblasts markers influence immune microenvironment in clear cell renal cell carcinoma.

BACKGROUND: Altered tumor microenvironment (TME) is characterized in clear cell renal cell carcinoma (ccRCC) as a result of the heterogeneity observed in the TME. Modulations in TME have shown tumor metastasis promotion; hence, identifying TME-based biomarkers can be critical for theranostics application. METHODS: Here, we performed an integrated systems biology approach utilizing differential gene expression, network metrics and clinical samples cohorts to prioritize the major deregulated genes and their associated pathways specific for metastasis. RESULTS: The gene expression profiling of 140 ccRCC samples resulted in 3657 differentially expressed genes, from which a network of 1867 up-regulated genes were further computed using network metrics for screening hub-genes. The specific pathways of ccRCC entailed through functional enrichment analysis of the hub-gene clusters indicated the role of the identified hub-genes in the enriched pathways, further validating the functional significance of the hub-genes. The positive correlation of TME cells, namely cancer-associated fibroblasts (CAFs) and its biomarkers (FAP and S100A4) with FN1, signified the role of hub-gene signaling for promoting metastasis in ccRCC. Thereafter, comparative expression, differential methylation, genetic alteration and overall survival analysis were analyzed to validate the screened hub-genes. CONCLUSIONS: The hub-genes were validated and prioritized by correlating with expression-based parameters, including histological grades, tumor, metastatic and pathological stages (based on median transcript per million; analysis of variance [ANOVA], P ≤ 0.05) from a clinically curated ccRCC dataset to further substantiate the translational benefits of the screened hub-genes as potential diagnostic biomarkers for ccRCC.

Translational protein RpsE as an alternative target for novel nucleoside analogues to treat MDR Enterobacter cloacae ATCC 13047: network analysis and molecular dynamics study.

The pathogenic Enterobacter cloacae subsp. cloacae str. ATCC 13047 has contemporarily emerged as a multi-drug resistant strain. To formulate an effective treatment option, alternative therapeutic methods need to be explored. The present study focused on Gene Interaction Network study of 46 antimicrobial resistance genes to reveal the densely interconnecting and functional hub genes in E. cloacae ATCC 13047. The AMR genes were subjected to clustering, topological and functional enrichment analysis, revealing rpsE (RpsE), acrA (AcrA) and arnT (ArnT) as novel therapeutic drug targets for hindering drug resistance in the pathogenic strain. Network topology further indicated translational protein RpsE to be exploited as a promising drug-target candidate for which the structure was predicted, optimized and validated through molecular dynamics simulations (MDS). Absorption, distribution, metabolism and excretion screening recognized ZINC5441082 (N-Isopentyladenosine) (Lead_1) and ZINC1319816 (cyclopentyl-aminopurinyl-hydroxymethyl-oxolanediol) (Lead_2) as orally bioavailable compounds against RpsE. Molecular docking and MDS confirmed the binding efficacy and protein-ligand complex stability. Furthermore, binding free energy (Gbind) calculations, principal component and free energy landscape analyses affirmed the predicted nucleoside analogues against RpsE protein to be comprehensively examined as a potential treatment strategy against E. cloacae ATCC 13047.

Comprehensive analysis on the diagnostic role of circulatory exosome-based miR-92a-3p for osteoblastic metastases in prostate adenocarcinoma.

Prostate adenocarcinoma (PRAD) is the second leading cause of death in men and the key factor that attributes to the severity and higher mortality rates is the tumor's ability to promote osteoblastic metastases (OM). Currently, no blood-based biomarkers are present that bridges the crosstalk between PRAD and OM progression. Conversely, circulatory microRNAs (miRNAs) are gaining interest among the scientific community for its potential as blood-based markers for cancer detection. Using computational pipeline, this study screened exosome-based miRNA that is functionally regulating OM in PRAD. We retrieved the expression profile of miRNA, mRNA from PRAD microarray, and RNA-Seq samples deposited in global repositories and identified the differentially expressed miRNAs (DEMs) and differentially expressed genes. Thereafter, the average expression of the miRNAs was identified in extracellular vesicle specifically in exosomes. Survival analysis and clinical profiling identified functionally significant miR-92a-3p to be a key factor in OM. This was further examined by the interactions with various noncoding RNA elements, transcription factors, oncogenes, tumor suppressor genes, and protein kinases regulated by miR-92a-3p. Identifying the expression pattern, nodal metastasis, Gleason score, and hazard ratio deciphered the critical role of the targets regulated by miR-92a-3p. Further, binding association analyzed through energy, seed match and accessibility showed the miRNA-targets involved in cytokine, TGF-ß, and Wnt signaling having close regulatory role in promoting OM. Our findings highlight the potent role of miR-92a-3p as blood-based diagnostic biomarker for OM. The comprehensive insights from our study can be elemental in designing diagnostic biomarker for PRAD.

Impact of the COVID-19 pandemic on routine vaccine landscape: A global perspective.

The coronavirus disease (COVID-19) threat is subsiding through extensive vaccination worldwide. However, the pandemic imposed major disruptions in global immunization programs and has aggravated the risks of vaccine-preventable disease (VPD) outbreaks. Particularly, lower-middle-income regions with minimal vaccine coverage and circulating vaccine-derived viral strains, such as polio, suffered additional burden of accumulated zero-dose children, further making them vulnerable to VPDs. However, there is no compilation of routine immunization disruptions and recovery prospects. There is a noticeable change in the routine vaccination coverage across different phases of the pandemic in six distinct global regions. We have summarized the impact of COVID-19 on routine global vaccination programs and also identified the prospects of routine immunization to combat COVID-like outbreaks.

Systems biology approach to understand the interplay between Bacillus anthracis and human host genes that leads to CVDs.

Humans infected with invasive Bacillus anthracis (B. anthracis) have a very poor prognosis and are at high risk for developing cardiovascular diseases (CVDs) and shock. Several bacterial elements probably have significant pathogenic roles in this pathogenic process of anthrax. In our current work, we have analysed the molecular level interactions between B. anthracis and human genes to understand the interplay during anthrax that leads to the CVDs. Our results have shown dense interactions between the functional partners in both host and the B. anthracis Gene interaction network (GIN). The functional enrichment analysis indicated that the clusters in the host GIN had genes related to hypoxia and autophagy in response to the lethal toxin; and genes related to adherens junction and actin cytoskeleton in response to edema toxin play a significant role in multiple stages of the disease. The B. anthracis genes BA_0530, guaA, polA, rpoB, ribD, secDF, metS, dinG and human genes ACTB, EGFR, EP300, CTNNB1, ESR1 have shown more than 50 direct interactions with the functional partners and hence they can be considered as hub genes in the network and they are observed to have important roles in CVDs. The outcome of our study will help to understand the molecular pathogenesis of CVDs in anthrax. The hub genes reported in the study can be considered potential drug targets and they can be exploited for new drug discovery.

Genomics and structural insight into the masking of gentamicin-resistance in clinical Burkholderia pseudomallei strain VB29710 from India.

The present study reported a rare gentamicin-susceptible ß-lactamase (PenA, OXA-57) expressing clinical Burkholderia pseudomallei isolate VB29710 from India. Whole-genome sequencing and structural analyses revealed the insertion of R962 and L963 into AmrB, the transmembrane-protein of the AmrAB-OprA efflux-pump that affected aminoglycoside-efflux through local alterations in backbone conformation.

Emergence of sulphonamide resistance in azithromycin-resistant pediatric strains of Salmonella Typhi and Paratyphi A: A genomics insight.

Whole genome sequences of Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) and Salmonella enterica subspecies enterica serovar Paratyphi A (S. Paratyphi A) from pediatric settings were used to assess the emerging Antimicrobial Resistance (AMR). The high throughput sequences of twenty pediatric clinical isolates of S. Typhi and S. Paratyphi A were retrieved and were screened for prevalent Antimicrobial Resistance Genes (ARGs) and Virulent Factors (VF). The resistance data was compared with the reference strains of S. Typhi and S. Paratyphi A. AMR studies identified sul1, sul2, dfrA7, tem-1, AH(6)-Id and APH(3″)-Ib as common ARGs. VFs were identified to understand the level of pathogenicity. The most prevalent AMR genes in the sequenced genomes were detected in phenotypically azithromycin-resistant S. Typhi. Correlation with the global genomes projected a trend of concurrent resistance to macrolides, ß lactams, fluoroquinolones (FQs), tetracyclines, ansamycins, and aminoglycosides. Traces of sulphonamide-resistance were observed indicating the emergence of a currently non-prevalent S. Typhi resistance that could be a future threat. Hence new antibiotic regimen to treat azithromycin-resistant S. Typhi should be formulated by avoiding the risks of aggravating sulphonamide resistance. The identified ARGs in genomes from paediatric isolates will aid future studies to design anti-bacterial compounds against S. Typhi and S. Paratyphi A.

Bioactive phytocompounds against specific target proteins of Borrelia recurrentis responsible for louse-borne relapsing fever: Genomics and structural bioinformatics evidence.

Louse-borne relapsing fever (LBRF) with high untreated mortality caused by spirochete Borrelia recurrentis is predominantly endemic to Sub-Saharan Africa and has re-emerged in parts of Eastern Europe, Asia and Latin America due to population migrations. Despite subtractive evolution of lice-borne pathogenic Borrelia spp. from tick-borne species, there has been no comprehensive report on conservation of protein targets across tick and lice-borne pathogenic Borrelia nor exploration of phytocompounds that are toxic to tick against lice. From the 19 available whole genomes including B. recurrentis, B. burgdorferi, B. hermsii, B. parkeri and B. miyamotoi, conservation of seven drug targets (>80% domain identity) viz. 30 S ribosomal subunit proteins (RSP) S3, S7, S8, S14, S19, penicillin-binding protein-2 and 50 S RSP L16 were deciphered through multiple sequence alignments. Twelve phytocompounds (hydroxy-tyrosol, baicalein, cis-2-decanoic acid, morin, oenin, rosemarinic acid, kaempferol, piceatannol, rottlerin, luteolin, fisetin and monolaurin) previously explored against Lyme disease spirochete B. burgdorferi when targeted against LBRF-causing B. recurrentis protein targets revealed high multi-target affinity (2%-20% higher than conventional antibiotics) through molecular docking. However, based on high binding affinity against all target proteins, stable coarse-grained dynamics (fluctuations <1 Å) and safe pharmacological profile, luteolin was prioritized. The study encourages experimental evaluation of the potent phytocompounds and similar protocols for investigating other emerging vector-borne diseases.