Binding selectivity analysis of new delhi metallo-beta-lactamase-1 inhibitors using molecular dynamics simulations: Exploring possibilities for decoding antimicrobial drug resistance.

BACKGROUND: New Delhi metallo-beta-lactamase-1 (NDM1) confers resistance to several bacterial species against a broad range of beta-lactam antibiotics and turning them into superbugs that pose a significant threat to healthcare systems worldwide. As such, it is a potentially relevant biological target for counteracting bacterial infections. Given the lack of effective treatment options against NDM1 producing bacteria, finding a reliable inhibitor for the NDM1 enzyme is crucial. METHODS: Using molecular dynamics simulations, the binding selectivities and affinities of three ligands, viz. PNK, 3S0, and N1G were investigated against NDM1. RESULTS: The results indicate that N1G binds with more affinity to NDM1 than PNK and 3S0. The binding energy decomposition analysis revealed that residues I35, W93, H189, K211, and N220 showed significant binding energies with PNK, 3S0, and N1G, and hence are crucially involved in the binding of the ligands to NDM1. Molecular dynamics trajectory analysis further elicited that the ligands influence dynamic flexibility of NDM1 morphology, which contributes to the partial selectivities of PNK, 3S0, and N1G. CONCLUSIONS: This in silico study offers a vital information for developing potential NDM1 inhibitors with high selectivity. Nevertheless, in vitro and in vivo experimental validation is mandated to extend the possible applications of these ligands as NDM1 inhibitors that succor in combating antimicrobial resistance.

Revolutionizing and identifying novel drug targets in Citrobacter koseri via subtractive proteomics and development of a multi-epitope vaccine using reverse vaccinology and immuno-informatics.

Citrobacter koseri is a gram-negative rod that has been linked to infections in people with significant comorbidities and immunocompromised immune systems. It is most commonly known to cause urinary tract infections. Thus, the development of an efficacious C. koseri vaccine is imperative, as the pathogen has acquired resistance to current antibiotics. Subtractive proteomics was employed during this research to identify potential antigenic proteins to design an effective vaccine against C. koseri. The pipeline identified two antigenic proteins as potential vaccine targets: DP-3-O-acyl-N-acetylglucosamine deacetylase and Arabinose 5-phosphate isomerase. B and T cell epitopes from the specific proteins were forecasted employing several immunoinformatic and bioinformatics resources. A vaccine was created using a combination of seven cytotoxic T cell lymphocytes (CTL), five helper T cell lymphocyte (HTL), and seven linear B cell lymphocyte (LBL) epitopes. An adjuvant (ß-defensin) was added to the vaccine to enhance immunological responses. The created vaccine was stable for use in humans, highly antigenic, and non-allergenic. The vaccine's molecular and interactions binding affinity with the human immunological receptor TLR3 were studied using MMGBSA, molecular dynamics (MD) simulations, and molecular docking analyses. E. coli (strain-K12) plasmid vector pET-28a (+) was used to examine the ability of the vaccine to be expressed. The vaccine shows great promise in terms of developing protective immunity against diseases, based on the results of these computer experiments. However, in vitro and animal research are required to validate our findings.Communicated by Ramaswamy H. Sarma.

Mucormycosis an added burden to Covid-19 Patients: An in-depth systematic review.

As of 25th July, 2022, global Disease burden of 575,430,244 confirmed cases and over 6,403,511 deaths have been attributed to coronavirus disease 2019 (COVID-19). Co-infections/secondary infections continue to plague patients around the world as result of the co-morbidities like diabetes mellitus, biochemical changes caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) especially significant elevation in free iron levels, immune suppression caused by SARS-CoV-2, and indiscriminate use of systemic corticosteroids for the treatment of severe COVID-19 disease. In such circumstances, opportunistic fungal infections pose significant challenge for COVID-19 disease therapy in patients with other co-morbidities. Although COVID-19-associated Mucormycosis (CAM) has been widely recognized, currently extensive research is being conducted on mucormycosis. It has been widely agreed that patients undergoing corticosteroid therapy are highly susceptible for CAM, henceforth high index of screening and intensive care and management is need of an hour in order to have favorable outcomes in these patients. Diagnosis in such cases is often delayed and eventually the disease progresses quickly which poses added burden to clinician and increases patient load in critical care units of hospitals. A vast perusal of literature indicated that patients with diabetes mellitus and those with other co-morbidities might be highly vulnerable to develop mucormycosis. In the present work, the case series of three patients presented at Chest Disease Hospital Srinagar, Jammu and Kashmir infected with CAM has been described with their epidemiological data in supplementary section. All these cases were found to be affected with co-morbidity of Diabetes Mellitus (DM) and were under corticosteroid therapy. Furthermore, given the significant death rate linked with mucormycosis and the growing understanding of the diseases significance, systematic review of the literature on CAM has been discussed and we have attempted to discuss emerging CAM and related aspects of the disease.

An insight in Salmonella typhi associated autoimmunity candidates' prediction by molecular mimicry.

Autoimmune diseases develop when the immune system targets healthy cells and tissues of an individual. In developing countries, S. typhi (a gram-negative pathogenic bacteria) remains a major public health issue. This study aimed to employ bioinformatics analyses to determine the 3D structural-based molecular mimicry and sequence of S. typhi and human host proteins. In addition, to classify possible antigenic microbial peptides homologous to human peptides and comprehend the molecular basis of S. typhi-related autoimmune disorders. Protein sequences were obtained from the NCBI database, and redundancy was removed using the CD-HIT tool. The BLASTp comparative sequence analysis was followed for molecular mimicry identification of human and S. typhi protein sequences. The PathDIP database was utilized to simulate essential physical relationships between proteins and curated pathways for metabolic processes. Subsequently, the IEDB database was used to find cross-reactive MHC class-II binding epitopes that could trigger an autoimmune reaction. SPARKS-X computational biology resource was also used to determine the structural homology between human and S. typhi peptides. The BLASTp study showed that S. typhi and the human host have several proteins holding considerable sequence similarities based on a set threshold of e ≤ 10-6 and bit score ≥100. The PathDIP putatively identified that these proteins enriched in a total of 68 metabolic pathways by a significant P-value (P < 0.005). The PSORTb analysis predicted that 26 out of these proteins are cytosolic, 1 predicted to be periplasmic protein, and 1 predicted to be localized in the cytoplasmic membrane. IEDB data analysis predicted many S.typhi and human homologs epitopes as a good binder of human HLA, i.e. DRB1*01:01, DPA1*03:01/DPB1*04:02, and DQA1*01:02/DQB1*06:02 with IC50 < 50 nM. Finally, the docking data demonstrated that homolog lead epitopes promisingly interact with HLA and immune TLR4 receptors by exhibiting the best docking scores and molecular interactions. The analyses ultimately identified several potential candidate proteins and peptides that could cause S.typhi infection-mediated autoimmune diseases in humans.

Antibiotic Susceptibility Patterns of ESßL Producers Isolated from the Mobile Phones.

Mobile phones have become an indispensable part of human lives for communication, education, and entertainment activities. This study aims to evaluate the diversity pattern of bacterial contaminants on mobiles and to check antibiotic resistance profiles in 105 samples. The study revealed a contamination of 51% in men and 49% in women, the highest in the 21- to 30-year age group, evidencing the extreme use of mobiles by teenagers. The study observed Gram-negative bacteria (63%) versus Gram-positive bacteria (37%). Overall, Gram-negative bacterial isolates showed the highest sensitivity to antibiotic nitrofurantoin (90%) and the lowest in ampicillin (35%). Gram positive has highest incidence of sensitivity towards tigecycline (100%) and lowest in cefoxitin (20%). ESßL producers were found to be 21.0% and highest being in Klebsiella oxytoca (35%) followed by Klebsiella pneumonia (31%). Staphylococcus pseudintermedius and Staphylococcus capitis have been identified on the mobile phones for the very first time. Interestingly, some soil microbes were also isolated and unfortunately found to have some antibiotic resistance like Raoultella ornithinolytica and Sphingomonas paucimobilis. The results revealed that mobiles were contaminated with multidrug-resistant (MDR) pathogens, and this study also showed that few of the saprophytic soil strains have antibiotic resistance, which can be an alarming situation that needs to be addressed.

Role of Antimicrobial Drug in the Development of Potential Therapeutics.

Population of the world run into several health-related emergencies among mankind and humans as it creates a challenge for the evolution of novel drug discoveries. One such can be the emergence of multidrug-resistant (MDR) strains in both hospital and community settings, which have been due to an inappropriate use and inadequate control of antibiotics that has led to the foremost human health concerns with a high impact on the global economy. So far, there has been application of two strategies for the development of anti-infective agents either by classical antibiotics that have been derived for their synthetic analogs with increased efficacy or screening natural compounds along with the synthetic compound libraries for the antimicrobial activities. However, need for newer treatment options for infectious diseases has led research to develop new generation of antimicrobial activity to further lessen the spread of antibiotic resistance. Currently, the principles aim to find novel mode of actions or products to target the specific sites and virulence factors in pathogens by a series of better understanding of physiology and molecular aspects of the microbial resistance, mechanism of infection process, and gene-pathogenicity relationship. The design various novel strategies tends to provide us a path for the development of various antimicrobial therapies that intends to have a broader and wider antimicrobial spectrum that helps to combat MDR strains worldwide. The development of antimicrobial peptides, metabolites derived from plants, microbes, phage-based antimicrobial agents, use of metal nanoparticles, and role of CRISPR have led to an exceptional strategies in designing and developing the next-generation antimicrobials. These novel strategies might help to combat the seriousness of the infection rates and control the health crisis system.