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

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, d...

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Main Authors: Mujawar, Shama *, Gatherer, Derek, Lahiri, Chandrajit *
Format: Article
Language:English
Published: Frontiers Media 2018
Subjects:
QH301 Biology
Online Access:http://eprints.sunway.edu.my/941/1/Lahiri%20Paradigm%20Shift%20in%20Drug%20Re%20purposing.pdf
http://eprints.sunway.edu.my/941/
http://doi.org/10.3389/fcimb.2018.00402
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spelling my.sunway.eprints.9412019-04-26T08:36:31Z http://eprints.sunway.edu.my/941/ Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi Mujawar, Shama * Gatherer, Derek Lahiri, Chandrajit * QH301 Biology 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. Frontiers Media 2018-11-14 Article PeerReviewed text en cc_by_nc_nd_4 http://eprints.sunway.edu.my/941/1/Lahiri%20Paradigm%20Shift%20in%20Drug%20Re%20purposing.pdf 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 http://doi.org/10.3389/fcimb.2018.00402 doi:10.3389/fcimb.2018.00402
institution Sunway University
building Sunway Campus Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Sunway University
content_source Sunway Institutional Repository
url_provider http://eprints.sunway.edu.my/
language English
topic QH301 Biology
spellingShingle QH301 Biology
Mujawar, Shama *
Gatherer, Derek
Lahiri, Chandrajit *
Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi
description 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.
format Article
author Mujawar, Shama *
Gatherer, Derek
Lahiri, Chandrajit *
author_facet Mujawar, Shama *
Gatherer, Derek
Lahiri, Chandrajit *
author_sort Mujawar, Shama *
title Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi
title_short Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi
title_full Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi
title_fullStr Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi
title_full_unstemmed Paradigm shift in drug re-purposing from Phenalenone to Phenaleno-Furanone to combat multi-drug resistant Salmonella Enterica Serovar Typhi
title_sort paradigm shift in drug re-purposing from phenalenone to phenaleno-furanone to combat multi-drug resistant salmonella enterica serovar typhi
publisher Frontiers Media
publishDate 2018
url http://eprints.sunway.edu.my/941/1/Lahiri%20Paradigm%20Shift%20in%20Drug%20Re%20purposing.pdf
http://eprints.sunway.edu.my/941/
http://doi.org/10.3389/fcimb.2018.00402
_version_ 1644324439577329664
score 13.211869

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