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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 (fluctuations1 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.

The synthesis of nanoparticles is an essential element of nanotechnology, because of its potential for use in chemotherapies, the interest in this area of research is expanding. For the synthesis of silver nanoparticles, the chemical reduction technique was used. According to these investigations, the particles have an average size of 16 nm and are mainly spherical in shape. Additionally, A dose-dependent cytotoxicity was also shown by the produced AgNPs against a human colon cancer cell line (HT29). At 72 hours of incubation, it was discovered that the inhibitory concentration (IC50) values for HT29 cells were 48.12 g/ml. The use of AO/EtBr labelling demonstrated an apoptotic induction. The current findings clearly suggested that HT29 cell lines treated with AgNPs would exhibit anticancer activity.

Anti-microbial resistance (AMR) creating healthcare concerns worldwide requires ardent exploration of therapeutic alternatives. Although anti-microbial peptides (AMP) are popular for broad-spectrum activity, recent evidence of increasing resistance to membrane-acting AMPs by ESKAPE pathogens has compelled us to design novel AMPs as therapeutic candidates. A library of 60 AMPs comprising natural AMPs and their mutants was constructed through in-silico methods. After physico-chemical property evaluations, each peptide in the library was subjected to flexible molecular docking against four major β-lactamases in Gram-negative ESKAPE pathogens. Among the potent AMP mutants, a Lactoferricin B-Mutant (M4) possessed uniformly high affinity with SHV1, OXA48, NDM1, and AmpC having energies -842.0Kcal/mol, -774.8Kcal/mol, -1103.3Kcal/mol, and -858.8Kcal/mol respectively. Coarse-grained clustering and flexibility analysis further accounted for the residue-level stable configurations of the protein-peptide complexes with high affinity. Highest affinity of Lactoferricin B_M4 was found with NDM1 due to H-bonds, salt-bridges, and hydrophobic interactions with the metallo-β-lactamase domain including crucial active-site residue Asp124. Molecular dynamics simulation further confirmed the stability of Lactoferricin B_M4-NDM1 complex having low residue-level root-mean square deviations (RMSD), atomic-level fluctuations, and radius of gyration (Rg). The study encourages experimental validations and similar methods to identify potential AMPs against drug-resistant pathogens.

Acinetobacter baumannii is an emerging nosocomial strain expressing extensive drug resistance (XDR). Whole-genome sequencing and molecular characterisation analysis revealed the presence of carbapenemase in 92.86% of studied Indian isolates having blaOXA-51, blaOXA-23, blaOXA-58, and blaNDM genes, with a few evidences of dual carbapenemase genes. As per the MLST scheme, IC2Oxf/CC2Pas was the predominant clone, with 57.14% isolates belonging to this lineage. The presence of β-lactamases has rendered sulbactam (SUL) resistance (MIC: 16-256µg/ml) in all the studied isolates. The efficacy of novel durlobactam (DUR) in inhibiting β-lactamases and PBP2 was assessed through in-silico inter-molecular interaction analysis. Several non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in PBP2 (G264S, I108V, S259T) and PBP3 (A515V, T526S) sequences. Minimal variations were recorded in the protein-backbone dynamics in active-site motifs of wild-type (WT) and mutants (MT), which correlated with the negligible binding energy fluctuations for PBP3-SUL (−5.85±0.04Kcal/mol) and PBP2-DUR (−5.16±0.66Kcal/mol) complexes. Furthermore, stronger binding affinities and low inhibition constants were noted in DUR complexed with OXA23 (−7.36Kcal/mol; 4.01µM), OXA58 (−6.44Kcal/mol; 19.07µM) and NDM (−6.82Kcal/mol; 10.01µM) when compared with conventional drugs avibactam and aztreonam. Stable interaction profiles of DUR, can possibly restore SUL activity against both PBP3WT and PBP3MTs. The study establishes the efficacy of novel SUL-DUR combination as a successful treatment strategy to combat emerging XDR strains.

Cancer has been constantly evolving and so is the research pertaining to cancer diagnosis and therapeutic regimens. Early detection and specific therapeutics are the key features of modern cancer therapy. These requirements can only be fulfilled with the integration of diverse high-throughput technologies. Integration of advanced omics methodology involving genomics, epigenomics, proteomics, and transcriptomics provide a clear understanding of multi-faceted cancer. In the past few years, tremendous high-throughput data have been generated from cancer genomics and epigenomic analyses, which on further methodological analyses can yield better biological insights. The major epigenetic alterations reported in cancer are DNA methylation levels, histone post-translational modifications, and epi-miRNA regulating the oncogenes and tumor suppressor genes. While the genomic analyses like gene expression profiling, cancer gene prediction, and genome annotation divulge the genetic alterations in oncogenes or tumor suppressor genes. Also, systems biology approach using biological networks is being extensively used to identify novel cancer biomarkers. Therefore, integration of these multi-dimensional approaches will help to identify potential diagnostic and therapeutic biomarkers. Here, we reviewed the critical databases and tools dedicated to various epigenomic and genomic alterations in cancer. The review further focuses on the multi-omics resources available for further validating the identified cancer biomarkers. We also highlighted the tools for cancer biomarker discovery using a systems biology approach utilizing genomic and epigenomic data. Biomarkers predicted using such integrative approaches are shown to be more clinically relevant.

In recent decades, antimicrobial resistance has been augmented as a global concern to public health owing to the global spread of multidrug-resistant strains from different ESKAPE pathogens. This alarming trend and the lack of new antibiotics with novel modes of action in the pipeline necessitate the development of non-antibiotic ways to treat illnesses caused by these isolates. In molecular biology, computational approaches have become crucial tools, particularly in one of the most challenging areas of multidrug resistance. The rapid advancements in bioinformatics have led to a plethora of computational approaches involving genomics, systems biology, and structural biology currently gaining momentum among molecular biologists since they can be useful and provide valuable information on the complex mechanisms of AMR research in ESKAPE pathogens. These computational approaches would be helpful in elucidating the AMR mechanisms, identifying important hub genes/proteins, and their promising targets together with their interactions with important drug targets, which is a crucial step in drug discovery. Therefore, the present review aims to provide holistic information on currently employed bioinformatic tools and their application in the discovery of multifunctional novel therapeutic drugs to combat the current problem of AMR in ESKAPE pathogens. The review also summarizes the recent advancement in the AMR research in ESKAPE pathogens utilizing the in silico approaches.

Emerging multi-drug resistance in recent Salmonella Typhi isolates, causative agent of enteric Typhoid fever, compelled us to investigate alternative therapeutic strategies. The present study encompassed virtual screening, ADMET screening as well as antibacterial activity prediction to shortlist potent lead molecules whose binding affinities (BAs) were checked against major druggable S. Typhi targets. BA profile revealed a deoxy-tetradeutero- curcumin derivative to be novel bioactive compound having high BA towards UDP-N-acetylmuramate-L-alanine ligase (MurC) protein involved in peptidoglycan synthesis. Molecular docking indicated that our lead {Binding energy (BE)= -8.00 ± 0.02 kcal/mol}could competitively bind to MurC with respect to its natural ligand ATP (BE= -7.65 ± 0.19 kcal/mol). The lead also possessed superior binding and inhibition profile against MurC than other commercial antibiotics. This BE was contributed by Hydrogen (H-) bonds and numerous non-canonical interactions with the evolutionary conserved active-site residues. From molecular docking and coarse-grained dynamics simulations, it was inferred that the novel curcumin derivative was predicted to be potential competitive inhibitor of ATP for MurC-catalytic domain having low relative RMSF (0.59 Å) to inhibit MurC-induced peptidoglycan biosynthesis. The inferences drawn from the study can open new portals for designing efficient therapeutic strategies against S. Typhi.

The present study reported a rare gentamicin-susceptible β-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.

Patients admitted to the hospital with coronavirus disease (COVID-19) are at risk for acquiring mycotic infections in particular Candidemia. Candida albicans (C. albicans) constitutes an important component of the human mycobiome and the most common cause of invasive fungal infections. Invasive yeast infections are gaining interest among the scientific community as a consequence of complications associated with severe COVID-19 infections. Early identification and surveillance for Candida infections is critical for decreasing the COVID-19 mortality. Our current study attempted to understand the molecular-level interactions between the human genes in different organs during systematic candidiasis. Our research findings have shed light on the molecular events that occur during Candidiasis in organs such as the kidney, liver, and spleen. The differentially expressed genes (up and down-regulated) in each organ will aid in designing organ-specific therapeutic protocols for systemic candidiasis. We observed organ-specific immune responses such as the development of the acute phase response in the liver; TGF-pathway and genes involved in lymphocyte activation, and leukocyte proliferation in the kidney. We have also observed that in the kidney, filament production, up-regulation of iron acquisition mechanisms, and metabolic adaptability are aided by the late initiation of innate defense mechanisms, which is likely related to the low number of resident immune cells and the sluggish recruitment of new effector cells. Our findings point to major pathways that play essential roles in specific organs during systemic candidiasis. The hub genes discovered in the study can be used to develop novel drugs for clinical management of Candidiasis.

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, β 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.

Aim: The rapid emergence of β-lactam resistance in gram-negative bacteria is a major problem in the treatment of infections caused by pathogenic bacterial strains, in particular Klebsiella pneumoniae. In our study, we are presenting a systems biology approach to understand the role of SHV-11 gene in drug resistance mechanism patterns in K. pneumoniae strain. Results: From the results, we have observed that the SHV-11 gene has a role in drug resistance mechanism along with its functional partner genes gyrA, parC, glsA, osmE, yjhA, yhdT, rimL, pepB, KPN_00437, and KPN_01875. We have also observed that of 51 genes, 27 genes were enriched in various Gene Ontology terms such as DNA metabolic process, DNA repair, and response to stress. The genes gyrA, parC, gyrB, parE, recA, dnaA, polB, dnaK, mutS, and dnaN constitute >41% of the total interactions; thus, these genes can be considered as hub nodes in the network, and they can be used as the potential drug targets. Conclusions: Drug exposure leads to the DNA damage in bacterial spp. We observed that the SHV11 gene along with the functional partners help in maintaining the genomic integrity by withstanding the environmental stress by inducing DNA damage repair mechanism. Our results provide a detailed understanding on the role of SHV-11 gene in drug resistance mechanisms in K. pneumoniae, and we are of the opinion that our results will be useful for researchers exploring the antibiotic resistance mechanisms in pathogenic bacteria.

Multi-drug resistant (MDR)The online version contains supplementary material available at 10.1007/s13205-022-03325-w.

The delayed diagnosis of pancreatic cancer has resulted in rising mortality rate and low survival rate that can be circumvented using potent theranostics biomarkers. The treatment gets complicated with delayed detection resulting in lowered 5-year relative survival rate. In our present study, we employed systems biology approach to identify central genes that play crucial roles in tumor progression. Pancreatic cancer genes collected from various databases were used to construct a statistically significant interactome with 812 genes that was further analysed thoroughly using topological parameters and functional enrichment analysis. The significant genes in the network were then identified based on the maximum degree parameter. The overall survival analysis indicated through hazard ratio [HR] and gene expression [log Fold Change] across pancreatic adenocarcinoma revealed the critical role of FN1 [HR 1.4; log2(FC) 5.748], FGA [HR 0.78; log2(FC) 1.639] FGG [HR 0.9; log2(FC) 1.597], C3 [HR 1.1; log2(FC) 2.637], and QSOX1 [HR 1.4; log2(FC) 2.371]. The functional significance of the identified hub genes signified the enrichment of integrin cell surface interactions and proteoglycan syndecan-mediated cell signaling. The differential expression, low overall survival and functional significance of FN1 gene implied its possible role in controlling metastasis in pancreatic cancer. Furthermore, alternate splice variants of FN1 gene showed 10 protein coding transcripts with conserved cell attachment site and functional domains indicating the variants' potential role in pancreatic cancer. The strong association of the identified hub-genes can be better directed to design potential theranostics biomarkers for metastasized pancreatic tumor.

The principal causative agent of acute bacterial meningitis (ABM) in children and the elderly is

The novel coronavirus SARS-CoV-2 since its emergence at Wuhan, China in December 2019 has been creating global health turmoil despite extensive containment measures and has resulted in the present pandemic COVID-19. Although the virus and its interaction with the host have been thoroughly characterized, effective treatment regimens beyond symptom-based care and repurposed therapeutics could not be identified. Various countries have successfully developed vaccines to curb the disease-transmission and prevent future outbreaks. Vaccination-drives are being conducted on a war-footing, but the process is time-consuming, especially in the densely populated regions of the world. Bioinformaticians and computational biologists have been playing an efficient role in this state of emergency to escalate clinical research and therapeutic development. However, there are not many reviews available in the literature concerning COVID-19 and its management. Hence, we have focused on designing a comprehensive review on in-silico approaches concerning COVID-19 to discuss the relevant bioinformatics and computational resources, tools, patterns of research, outcomes generated so far and their future implications to efficiently model data based on epidemiology; identify drug targets to design new drugs; predict epitopes for vaccine design and conceptualize diagnostic models. Artificial intelligence/machine learning can be employed to accelerate the research programs encompassing all the above urgent needs to counter COVID-19 and similar outbreaks.

BackgroundThe incidence of hypervirulent (hv) carbapenem-resistant (CR)Klebsiella pneumoniae(Kp) is increasing globally among various clones and is also responsible for nosocomial infections. The CR-hvKp is formed by the uptake of a virulence plasmid by endemic high-risk clones or by the uptake of plasmids carrying antimicrobial resistance genes by the virulent clones. Here, we describe CR-hvKp from India belonging to high-risk clones that have acquired a virulence plasmid and are phenotypically unidentified due to lack of hypermucoviscosity.MethodsTwenty-seven CRKp isolates were identified to possessrmpA2by whole-genome sequencing; and resistance and virulence determinants were characterized. Byin silicoprotein modeling (and validation), protein backbone stability analysis, and coarse dynamics study, the fitness of RmpA, RmpA2, and aerobactin-associated proteins-IucA and IutA, were determined to establish a reliable marker for clinical identification of CR-hvKp.ResultsThe CR-hvKp belonged to multidrug-resistant (MDR) high-risk clones such as CG11, CG43, ST15, and ST231 and carried OXA-232 as the predominant carbapenemase followed by NDM. The virulence plasmid belonged to IncHI1B replicon type and carried frameshifted and truncatedrmpAandrmpA2. This resulted in a lack of hypermucoviscous phenotype. However, functional aerobactin was expressed in all high-risk clones.In silicoanalysis portrayed that IucA and IutA were more stable than classical RmpA. Furthermore, IucA and IutA had lower conformational fluctuations in the functional domains than the non-functional RmpA2, which increases the fitness cost of the latter for its maintenance and expression among CR-hvKp. Hence, RmpA and RmpA2 are likely to be lost among CR-hvKp owing to the increased fitness cost while coding for essential antimicrobial resistance and virulence factors.ConclusionIncreasing incidence of convergence of AMR and virulence is observed amongK. pneumoniaeglobally, which warrants the need for reliable markers for identifying CR-hvKp. The presence of non-functional RmpA2 among high-risk clones highlights the significance of molecular identification of CR-hvKp. The negative string test due to non-functional RmpA2 among CR-hvKp isolates challenges phenotypic screening and faster identification of this pathotype. This can potentially be counteracted by projecting aerobactin as a stable, constitutively expressed, and functional marker for rapidly evolving CR-hvKp.

Streptococcus pneumoniae is the principal etiological agent of acute bacterial meningitis (ABM) which has fatal outcome in children and elderly. Due to poor blood-brain barrier (BBB) permeation, conventional β-lactam antibiotics fail to establish the requisite bactericidal concentration in central nervous system leading to resistance in meningeal infections. The present study intended to identify potential therapeutic alternatives against Streptococcal meningitis.Virtual screening, pharmacokinetics/pharmacodynamics (PK/PD) and anti-bacterial evaluations were employed to screen potential drugs. Molecular docking and structural dynamics simulations were performed to analyze the binding affinity and interaction stability of the drugs against the conventional Penicillin binding protein (PBP) targets. Screened drugs were also checked for interactions with other possible Streptococcal targets and relevant host targets.Non-steroidal anti-inflammatory drugs (NSAIDs) ketorolac and etodolac exhibiting high BBB-permeation and anti-bacterial potency were identified. Ketorolac and etodolac possessed uniform binding affinities against PBP1A, PBP2X, PBP2B and PBP3 with low inhibition constants (50 μM). Against PBP2B and PBP3, higher binding affinities were observed for ketorolac (-6.45 and -6Kcal/mol respectively) and etodolac (-6.36 and -6.55Kcal/mol respectively) than penicillin (-5.95 and -5.85Kcal/mol respectively) and cefotaxime (-5.08 and -5.07Kcal/mol respectively). The binding affinities were contributed by conventional H-bonds and non-canonical interactions with active site residues of PBPs. Structural dynamics simulations further indicated the overall stability of the drug-bound complexes through minimal overall average root-mean square fluctuations (RMSFs) (1.0 Å). The average binding affinities of Ketorolac and Etodolac with PBPs were marginally higher than other Streptococcal targets and comparable to their conventional inflammatory targets.Pharmacological and structural profiles indicated that ketorolac and etodolac can potentially subdue the cause and effects of streptococcal meningitis and hence encourage experimental validations.

Metallo-β-lactamases (MBLs) producing bacteria especially the ones with New Delhi metallo-beta-lactamase-1 (NDM-1) and its variants can potentially hydrolyse all the major β-lactam antibiotics, ultimately escalating anti-microbial resistance world-wide. There is a dearth of approved inhibitors to combat NDM and other MBLs producing bacteria. Hence we focussed to find novel inhibitor(s) in-silico which can potentially suppress the activity of NDM/MBLs. A total of 2400 compounds were virtually screened to identify a promising carboxylic acid-containing compound (CID-53986787) analogous to NDM antagonist Captopril. Our lead compound can bind adjacent to the active site zinc ions (Zn1 and Zn2) in all highly resistant NDM variants. CID-53986787 possesses ~ 5–8% higher binding affinity than Captopril, exhibiting molecular interactions with crucial residues that can destabilize the hydrolytic activity of NDM. CID-53986787 was virtually evaluated to ascertain its safe pharmacological/toxicity profile. Molecular dynamics simulation studies further elucidated its stable interaction with the target protein (NDM-1).

Malaria is the major health issue in African, Asian and Mediterranean regions of the world. Due to the emerging resistance by the parasites and mosquitoes for the current medications and insecticid...

The emergence of multidrug resistance (MDR), extensively drug-resistant, and total drug-resistant Mycobacterium tuberculosis (Mtb) strains have hampered the treatment of tuberculosis (TB). Capreomycin and Bedaquiline are currently used for MDR-TB treatment. To understand the impact of these antibiotics on Mtb genes, we have curated the gene expression data where the Mtb cultures were exposed to the Bedaquiline and Capreomycin. Based on the P value cut off (0.05) and logFC (-0.5 and+0.5) values, we have selected the top differentially expressed genes during the antibiotic exposures. We have observed that the top differentially expressed Mtb genes were related to universal stress genes, two-component regulatory systems, and drug efflux pumps. We have curated the Mtb gene datasets and carried out the functional over-representation analysis using the individual gene expression values. We further, constructed the gene interaction networks of antibiotic resistance genes and virulence genes of Mtb to understand the impact of the antibiotics at the molecular level and thus to understand the antimicrobial resistance and virulence patterns. Our study elucidates the impact of antibiotics on the Mtb genes at the molecular level and the positively enriched pathways, operons, and regulons data are helpful in understanding the resistance patterns in Mtb. The upregulated genes during the exposure of Bedaquiline and Capreomycin can be considered as potent drug targets for the development of new anti-TB drugs.

Klebsiella pneumoniae (K. pneumoniae) is a Gram-negative bacterium, which is a leading causal agent for nosocomial infections. Penicillin, cephalosporin and carbapenems along with the inhibitors such as tazobactam, sulbactam and clavulanic acid are prescribed for the treatment of K. pneumoniae infections. Prolonged exposure to β-lactam antibiotics leads to the development of resistance. The major reason for the β-lactam resistance in K. pneumoniae is the secretion of the enzyme K. pneumoniae carbapenemase (KPC). Secretion of KPC-2 and its variant KPC-3 by the K. pneumoniae strains causes resistance to both the substrate imipenem and the β-lactamase inhibitors. Hence, molecular docking and dynamics studies were carried out to analyze the resistance mechanism of KPC-2-imipenem and KPC-3-imipenem at the structural level. It reveals that KPC-3-imipenem has the highest c-score value of 4.03 with greater stability than the KPC-2-imipenem c-score value of 2.36. Greater the interaction between the substrate and the β-lactamase enzyme, higher the chances of hydrolysis of the substrate. Presently available β-lactamase inhibitors are also ineffective against KPC-3-expressing strains. This situation necessitates the need for development of novel and effective inhibitors for KPC-3. We have carried out the virtual screening process to identify more effective inhibitors for KPC-3, and this has resulted in ZINC48682523, ZINC50209041 and ZINC50420049 as the best binding energy compounds, having greater binding affinity and stability than KPC-3-tazobactam interactions. Our study provides a clear understanding of the mechanism of drug resistance and provides valuable inputs for the development of inhibitors against KPC-3 expressing K. pneumoniae. Communicated by Ramaswamy H. Sarma.

BAG3, a co-chaperone protein with a Bcl-2-associated athanogene (BAG) domain, has diverse functionalities in protein-folding, apoptosis, inflammation, and cell cycle regulatory cross-talks. It has been well characterised in cardiac diseases, cancers, and viral pathogenesis. The multiple roles of BAG3 are attributed to its functional regions like BAG, Tryptophan-rich (WW), isoleucine-proline-valine-rich (IPV), and proline-rich (PXXP) domains. However, to study its structural impact on various functions, the experimental 3D structure of BAG3 protein was not available. Hence, the structure was predicted through in silico modelling and validated through computational tools and molecular dynamics simulation studies. To the best of our knowledge, the role of BAG3 in bacterial infections is not explicitly reported. We attempted to study them through an in-silico protein-protein interaction network and host-pathogen interaction analysis. From structure-function relationships, it was identified that the WW and PXXP domains were associated with cellular cytoskeleton rearrangement and adhesion-mediated response, which might be involved in BAG3-related intracellular bacterial proliferation. From functional enrichment analysis, Gene Ontology terms and topological matrices, 18 host proteins and 29 pathogen proteins were identified in the BAG3 interactome pertaining to Legionellosis, Tuberculosis, Salmonellosis, Shigellosis, and Pertussis through differential phosphorylation events associated with serine metabolism. Furthermore, it was evident that direct (MAPK8, MAPK14) and associated (MAPK1, HSPD1, NFKBIA, TLR2, RHOA) interactors of BAG3 could be considered as therapeutic markers to curb down intracellular bacterial propagation in humans.

Background Cardiovascular Disease (CVD) is one of the most common causes of mortality in humans. Presently, the role of pathogens in the initiation and progression of the CVDs is not clearly understood. Hence, it is essential to understand the molecular-level interactions between the human proteins and the microbial proteins to deduce their functional roles in the CVDs. Method The host-pathogen interactions (HPI) related to CVDs in the case of E. coli str. O157:H7 colonization were curated, and also the protein-protein interactions (PPI) between humans and E. coli were collected. Gene interaction network (GIN) and functional enrichment analyses (FEA) were utilized for this. Results The GIN revealed dense interactions between the functional partners. The FEA indicated that the essential pathways played a significant role in humans as well as in E. coli. The primary responses against most of the bacterial pathogens in humans are different from that of E. coli; Terpenoid biosynthesis and production of secondary metabolite pathways aid the survival of the E. coli inside the host. Interestingly, network analysis divulged that the E. coli genes ksgA, rpsT, ispE, rpsI, ispH, and the human genes TP53, CASP3, CYCS, EP300, RHOA communicated by significant numbers in direct interactions. Conclusions The results obtained from the present study will help researchers understand the molecular-level interactions in the CVDs between the human and the E. coli genes. The important genes with vital interactions can be considered as hub molecules and can be exploited for new drug discovery.

No commercially available drug candidate has yet been devised which is unique to and not repurposed against SARS-CoV-2 and has high efficacy or safe toxicity profile or both. Taking curcumin as a reference compound, we identified a new commercially available cyclohexanone compound, ZINC07333416 with binding energy (−8.72 kcal/mol) better than that of popularly devised anti-Covid-19 drugs like viral protease inhibitor Lopinavir, nucleoside analogue Remdesivir and the repurposed drug hydroxychloroquine when targeted to the active-site of SARS-CoV-2 Main protease (Mpro) through docking studies. The ligand ZINC07333416 exhibits crucial interactions with major active site residues of SARS-CoV-2 Mpro viz. Cys145 and His41 involving in the protease activity; as well as GLU-166 and ASN-142 which plays the pivotal role in the protein-dimerization. The protein-ligand stable interaction was further confirmed with molecular dynamics simulation (MDS) studies. Based on virtual assessment, ZINC07333416 also have significant values in terms of medicinal chemistry, pharmacokinetics, synthetic accessibility and anti-viral activity that encourage its experimental applications against COVID-19., Highlights •We screened commercially available compounds with curcumin as a reference to specifically pertain to the anti-viral potential and safe toxicity profile of the later. •We checked the binding properties of lead compound and previously reported compounds against SARS-CoV-2 Mpro, besides comparing their pharmacological and toxicity profile. A novel cyclohexanone compound was identified with favourable drug attributes and eliciting stable molecular interactions with SARS-CoV-2 Mpro.

Proteus mirabilis is one among the most frequently identified pathogen in patients with the urinary tract infection. The multidrug resistance exhibited by P. mirabilis renders the treatment ineffective, and new progressive strategies are needed to overcome the antibiotic resistance (AR). We have analyzed the evolutionary relationship of 29 P. mirabilis strains available in the National Center for Biotechnology Information-Genome database. The antimicrobial resistance genes of P. mirabilis along with the enriched pathways and the Gene Ontology terms are analyzed using gene networks to understand the molecular basis of AR. The genes rpoB, tufB, rpsl, fusA, and rpoA could be exploited as potential drug targets as they are involved in regulating the vital functions within the bacterium. The drug targets reported in the present study will aid researchers in developing new strategies to combat multidrug-resistant P. mirabilis.