Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi

Mujawar, Shama * and Gatherer, Derek and Lahiri, Chandrajit * (2018) Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi. Frontiers in Cellular and Infection Microbiology, 8. ISSN 2235-2988

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Over recent years, typhoid fever has gained increasing attention with several cases reporting treatment failure due to multidrug resistant (MDR) strains of Salmonella enterica serovar Typhi. While new drug development strategies are being devised to combat the threat posed by these MDR pathogens, drug repurposing or repositioning has become a good alternative. The latter is considered mainly due to its capacity for saving sufficient time and effort for pre-clinical and optimization studies. Owing to the possibility of an unsuccessful repositioning, due to the mismatch in the optimization of the drug ligand for the changed biochemical properties of “old” and “new” targets, we have chosen a “targeted” approach of adopting a combined chemical moiety-based drug repurposing. Using small molecules selected from a combination of earlier approved drugs having phenalenone and furanone moieties, we have computationally delineated a step-wise approach to drug design against MDR Salmonella. We utilized our network analysisbased pre-identified, essential chaperone protein, SicA, which regulates the folding and quality of several secretory proteins including the Hsp70 chaperone, SigE. To this end, another crucial chaperone protein, Hsp70 DnaK, was also considered due to its importance for pathogen survival under the stress conditions typically encountered during antibiotic therapies. These were docked with the 19 marketed anti-typhoid drugs along with two phenalenone-furanone derivatives, 15 non-related drugs which showed 70% similarity to phenalenone and furanone derivatives and other analogous small molecules. Furthermore, molecular dynamics simulation studies were performed to check the stability of the protein-drug complexes. Our results showed the best binding interaction and stability, under the parameters of a virtual human body environment, with XR770, a phenaleno-furanone moiety based derivative. We therefore propose XR770, for repurposing for therapeutic intervention against emerging and significant drug resistance conferred by pathogenic Salmonella strains.

Item Type: Article
Uncontrolled Keywords: drug repurposing; salmonellosis; multidrug resistance; chaperones; SicA; DnaK
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Others > Non Sunway Academics
Sunway University > School of Engineering and Technology [formerly School of Science and Technology until 2020] > Dept. Biological Sciences moved to SMLS wef 2021
Depositing User: Dr Janaki Sinnasamy
Related URLs:
Date Deposited: 22 Nov 2018 03:43
Last Modified: 26 Apr 2019 08:36

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