Shama Najir, Ahmed Mujawar (2019) Computational analyses of putative drug targets and vaccine candidates against clinically important multidrug resistant bacterial pathogens. Doctoral thesis, Sunway University.
Full text not available from this repository.Abstract
Bacterial multidrug resistance (MDR) poses major threats to the global human health as described by the World Health Organization (WHO). Conceptually, MDR reflects the ability of bacterial pathogens to combat deadly doses of structurally different antibiotics, which are supposedly used for killing the sensitive strains. Based on previous reports, we have explored different mechanisms known to be involved in drug resistance. These were computationally analyzed to reveal the crucial role players that could be used as drug targets and/or vaccine candidates by future researchers. Essentially, we have integrated four different approaches to explore for the crucial virulent proteins which might be involved in the mechanism causing MDR in bacteria. For example, in this study, we have dealt with the efflux pumps proteins viz. AcrA, AcrB, AcrD, MdtA, MdtB, MdtC, the signal transduction proteins like BaeS, BaeR, the chaperone proteins viz. SicA, DnaK, SigE and other proteins involved in biofilm formation pathways to propose a four-approach based intervention strategy for managing MDR. These approaches were rationally interlinked through screening and identification of drug targets and/or vaccine candidates from the protein interactomes of either virulence factors and pathways present in certain virulent phenotypes or whole genomes of selected alarming MDR bacterial species. These candidates were verified through variant analyses of archived infected patient’s bacterial samples to decipher potential drug binding sites. One such unanimously affected target is revealed to be DnaK from Salmonella enterica serovar Typhimurium, Acinetobacter baumannii, Proteus mirabilis, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae and Mycobacterium tuberculosis. To this end, DnaK has been phylogenetically analyzed to be co-evolved with other house-keeping genes upon exhibiting complete clade matches with the 16S rDNA tree across the aforementioned species. Finally, DnaK was found to be inhibited by our screened and proposed ligand XR770, a phenaleno-furanone derivative, to exhibit the highest binding affinity in the active site wherein the amino acid change was found to be located in DnaK. For instance, our study revealed dnaK gene to contain a mutation at position 723401 with the nucleotide changing from C to A causing a change in the amino acid, thereby altering the normal function of the DnaK protein in MDR Salmonella species. Hence, we propose DnaK, to be the plausible target site with the potential for new therapeutic interventions in combating MDR for the selected MDR pathogens.
| Item Type: | Thesis (Doctoral) |
|---|---|
| Subjects: | Q Science > QR Microbiology |
| Divisions: | Sunway University > School of Medical and Life Sciences [formerly School of Healthcare and Medical Sciences until 2020] > Dept. Biological Sciences |
| Depositing User: | Ms Yong Yee Chan |
| Date Deposited: | 27 Sep 2023 02:02 |
| Last Modified: | 27 Sep 2023 02:02 |
| URI: | http://eprints.sunway.edu.my/id/eprint/2383 |
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