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Genomic analysis of Chryseobacterium indologenes and conformational dynamics of the selected DD-peptidase
Muhammad Irfan1, Muhammad Tariq2, Zarrin Basharat1
1Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
Abstract:
Chrysobacterium indologenes is an emerging MDR pathogen that belongs to the family Flavobacteriaceae. The genome of the C. indologenes, isolated from the nephrotic patient, was sequenced through Illumina MiSeq. The pangenomics of available 56 C. indologenes strains using BPGA revealed an open pangenome (n=5553 CDS), core genome (2141), and accessory genome (2013). The CEG/DEG database identified 662 essential genes that drastically reduced to 68 genes after non-homology analyses towards human and gut microbiome. Further filtering the data for other drug target prioritizing parameters resulted in 32 putative targets. Keeping in view the crucial role played in cell wall biosynthesis, dacB was selected as the final target that encodes D-alanyl-d-alanine carboxypeptidase/endopeptidase (DD-peptidase). The 3D structure of dacB was modelled and rendered to docking analyses against two compound libraries of African plants (n=6842) and Tibetan medicines (n=52). The ADMET profiling exhibited the physicochemical properties of final compounds. The MD simulations showed the stability of inhibitor-DD-peptidase complex and interactions in terms of RMSD, RMSF, binding free energy calculation and H-bonding. We propose that the novel compounds Leptopene and ZINC95486338 from our findings might be potent DD-peptidase inhibitors that could aid in the development of new antibiotic-resistant therapy for the emerging MDR C. indologenes.
Insights
Chrysobacterium indologenes, a multidrug-resistant pathogen, was analyzed using pangenomics to identify essential genes. Researchers identified dacB as a potential drug target, with novel compounds showing promise for new antibiotic therapies.
Area of Science:
- Microbiology
- Genomics
- Drug Discovery
Background:
- Chrysobacterium indologenes is an emerging multidrug-resistant (MDR) pathogen.
- Genomic analysis is crucial for understanding MDR mechanisms and identifying therapeutic targets.
Purpose of the Study:
- To perform pangenomics of Chrysobacterium indologenes strains.
- To identify essential genes and potential drug targets for combating MDR C. indologenes.
- To discover novel inhibitors for the dacB gene product, a D-alanyl-d-alanine carboxypeptidase/endopeptidase.
Main Methods:
- Genome sequencing and pangenomic analysis of 56 C. indologenes strains.
- Identification of essential genes using CEG/DEG database and non-homology analysis.
- 3D structure modeling of dacB and molecular docking against African plant and Tibetan medicine libraries.
- ADMET profiling and molecular dynamics simulations to assess compound stability and interactions.
Main Results:
- Pangenomic analysis revealed an open pangenome with 5553 CDS.
- 662 essential genes were identified, reduced to 68 after filtering, leading to 32 putative drug targets.
- The dacB gene, encoding DD-peptidase, was selected as a key target.
- Novel compounds Leptopene and ZINC95486338 showed potential as DD-peptidase inhibitors.
Conclusions:
- The study identified dacB as a promising drug target against MDR Chrysobacterium indologenes.
- Leptopene and ZINC95486338 are proposed as potential lead compounds for developing new antibiotic therapies.
- This research contributes to strategies for combating emerging antibiotic resistance.
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