[Final accepted version, edited] Redefining genomic view of Clostridioides difficile through pangenome analysis and identification of drug targets from its core genome

Abstract

Introduction: Clostridioides difficile infection (CDI) is a leading cause of gastrointestinal infections and in the present day is a major concern for global health care system. The unavailability of specific antibiotics for CDI treatment and its emerging cases worldwide further broaden the challenge to control CDI. Methods: The availability of a large number of genome sequences for C. difficile and many bioinformatics tools for genome analysis provides the opportunity for in silico pangenomic analysis. In the present study, 97 strains of C. difficilewere used for pangenomic studies and characterized for their phylogenomic and functional analysis. Results: Pangenome analysis reveals open pangenome of C. difficile and high genetic diversity. Sequence and interactome analysis of 1,481 core genes was done and eight potent drug targets are identified. Three drug targets, namely, aminodeoxychorismate synthase (PabB), d-alanyl-d-alanine carboxypeptidase (DD-CPase) and undecaprenyl diphospho-muramoyl pentapeptide beta-N-acetylglucosaminyl transferase (MurG transferase), have been reported as drug targets for other human pathogens, and five targets, namely, bifunctional diguanylate cyclase/phosphodiesterase (cyclic-diGMP), sporulation transcription factor (Spo0A), histidinol-phosphate transaminase (HisC), 3-deoxy-7-phosphoheptulonate synthase (DAHP synthase) and c-di-GMP phosphodiesterase (PdcA), are novel. Conclusion: The suggested potent targets could act as broad-spectrum drug targets for C. difficile. However, further validation needs to be done before using them for lead compound discovery.

Genomic study of European Clostridioides difficile ribotype 002/sequence type 8

“…The [72][73][74][75]. Additionally, differences in the gene cutoffs used to classify core and pangenomes, the number of genomes included, strain sources, diversity, and sampling strategy may influence the estimates of the pangenome.…”

“…Nevertheless, it is important to be careful when comparing pangenome results from different studies involving other C. difficile lineages, as different software tools might be accountable for divergent results [49, 72, 73]. However, even though the software panaroo delivers smaller pangenomes ( C. difficile species pangenome with panaroo: 17, 470 genes; with Roary: 32, 802 genes), with a higher proportion of the core genome, the lineage ST8/RT002 still possessed an open genome as described for other C. difficile lineages and for the C. difficile species in general [72–75]. Additionally, differences in the gene cutoffs used to classify core and pangenomes, the number of genomes included, strain sources, diversity, and sampling strategy may influence the estimates of the pangenome.…”

Human Pangenomics: Promises and Challenges of a Distributed Genomic Reference

“…A focus on core genes, for instance, considers only those that are shared by all members of the population and disregards the variability of the accessory genome. This model is useful for framing the stability and resilience of a population in changing environmental conditions by identifying shared or conserved genomic elements and can be used to pinpoint common druggable targets for antibiotic therapy [ 42 , 44 , 45 ]. An expanded model, on the other hand, may consider the variability of the accessory genome and provide a more accurate description of the genetic repertoire of a species, highlighting the emergence of novel genes by selection and adaptation [ 46 ].…”

Molecular docking, dynamics and in vitro analysis of multi-target inhibitors for Clostridioides difficile

“…As the therapeutic antimicrobial options are limited for CDI due to its rising antibiotic resistance and declining sensitivity, there is an urgent need for the development of novel anti-clostridial drugs [ 17 , 18 , 19 , 20 , 21 ]. Five proteins of C difficile that were reported as drug targets were used [ 22 ]. Therefore, it is of interest to report the molecular docking, dynamics and in vitro analysis of multi-target inhibitors for Clostridioides difficile .…”