Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study

Farnesol, a self-secreted quorum-sensing molecule (QSM) of Candida albicans, has been known to limit yeast-to-hyphal transition by blocking the RAS1–cAMP–PKA pathway. In a similar fashion, certain bacterial QSMs have also been reported to be successful in attenuating C. albicans biofilm and hyphal f...

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Autores principales:	Ravi Jothi, Nagaiah Hari Prasath, Shanmugaraj Gowrishankar, Shunmugiah Karutha Pandian
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	quorum-sensing molecules farnesol C. albicans diketopiperazines dimorphism antihyphal Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/48a398096dfa4aa5b6b10ff2c34efb34
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spelling	oai:doaj.org-article:48a398096dfa4aa5b6b10ff2c34efb342021-12-03T04:47:15ZBacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study2235-298810.3389/fcimb.2021.781790https://doaj.org/article/48a398096dfa4aa5b6b10ff2c34efb342021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcimb.2021.781790/fullhttps://doaj.org/toc/2235-2988Farnesol, a self-secreted quorum-sensing molecule (QSM) of Candida albicans, has been known to limit yeast-to-hyphal transition by blocking the RAS1–cAMP–PKA pathway. In a similar fashion, certain bacterial QSMs have also been reported to be successful in attenuating C. albicans biofilm and hyphal formation at relatively high cell density. This prompted us to investigate the antihyphal efficacy of certain bacterial QSMs through virtual docking against seminal drug targets, viz., CYCc and RAS1, that have been reported to be the hallmark players in C. albicans dimorphic virulence cascade. Against this backdrop, 64 QSMs belonging to five different bacterial QS signaling systems were subjected to initial virtual screening with farnesol as reference. Data of the virtual screening unveiled QSMs belonging to diketopiperazines (DKPs), i.e., 3-benzyl-6-isobutylidene-2,5-piperazinedione (QSSM 1157) and cyclo(l-Pro-l-Leu) (QSSM 1112), as potential inhibitors of CYCc and RAS1 with binding energies of −8.2 and −7.3 kcal mol−1, respectively. Further, the molecular dynamics simulations (for 50 ns) of CYCc-QSSM 1157 and RAS1-QSSM 1112 complexes revealed the mean ligand root mean square deviation (RMSD) values of 0.35 and 0.27 Å, respectively, which endorsed the rigid nature, less fluctuation in binding stiffness, and conformation of binding complexes. Furthermore, the identified two QSMs were found to be good in solubility, absorption, and permeation and less toxic in nature, as revealed by pharmacokinetics and toxicity analyses. In addition, the in vitro antihyphal assays using liquid and solid media, germ-tube experiment, and microscopic analysis strongly validated DKP-QSSM 1112 as a promising inhibitor of hyphal transition. Taken together, the present study unequivocally proves that DKPs can be used as potent inhibitors of C. albicans virulence dimorphism.Ravi JothiNagaiah Hari PrasathShanmugaraj GowrishankarShunmugiah Karutha PandianFrontiers Media S.A.articlequorum-sensing moleculesfarnesolC. albicansdiketopiperazinesdimorphismantihyphalMicrobiologyQR1-502ENFrontiers in Cellular and Infection Microbiology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	quorum-sensing molecules farnesol C. albicans diketopiperazines dimorphism antihyphal Microbiology QR1-502
spellingShingle	quorum-sensing molecules farnesol C. albicans diketopiperazines dimorphism antihyphal Microbiology QR1-502 Ravi Jothi Nagaiah Hari Prasath Shanmugaraj Gowrishankar Shunmugiah Karutha Pandian Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study
description	Farnesol, a self-secreted quorum-sensing molecule (QSM) of Candida albicans, has been known to limit yeast-to-hyphal transition by blocking the RAS1–cAMP–PKA pathway. In a similar fashion, certain bacterial QSMs have also been reported to be successful in attenuating C. albicans biofilm and hyphal formation at relatively high cell density. This prompted us to investigate the antihyphal efficacy of certain bacterial QSMs through virtual docking against seminal drug targets, viz., CYCc and RAS1, that have been reported to be the hallmark players in C. albicans dimorphic virulence cascade. Against this backdrop, 64 QSMs belonging to five different bacterial QS signaling systems were subjected to initial virtual screening with farnesol as reference. Data of the virtual screening unveiled QSMs belonging to diketopiperazines (DKPs), i.e., 3-benzyl-6-isobutylidene-2,5-piperazinedione (QSSM 1157) and cyclo(l-Pro-l-Leu) (QSSM 1112), as potential inhibitors of CYCc and RAS1 with binding energies of −8.2 and −7.3 kcal mol−1, respectively. Further, the molecular dynamics simulations (for 50 ns) of CYCc-QSSM 1157 and RAS1-QSSM 1112 complexes revealed the mean ligand root mean square deviation (RMSD) values of 0.35 and 0.27 Å, respectively, which endorsed the rigid nature, less fluctuation in binding stiffness, and conformation of binding complexes. Furthermore, the identified two QSMs were found to be good in solubility, absorption, and permeation and less toxic in nature, as revealed by pharmacokinetics and toxicity analyses. In addition, the in vitro antihyphal assays using liquid and solid media, germ-tube experiment, and microscopic analysis strongly validated DKP-QSSM 1112 as a promising inhibitor of hyphal transition. Taken together, the present study unequivocally proves that DKPs can be used as potent inhibitors of C. albicans virulence dimorphism.
format	article
author	Ravi Jothi Nagaiah Hari Prasath Shanmugaraj Gowrishankar Shunmugiah Karutha Pandian
author_facet	Ravi Jothi Nagaiah Hari Prasath Shanmugaraj Gowrishankar Shunmugiah Karutha Pandian
author_sort	Ravi Jothi
title	Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study
title_short	Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study
title_full	Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study
title_fullStr	Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study
title_full_unstemmed	Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study
title_sort	bacterial quorum-sensing molecules as promising natural inhibitors of candida albicans virulence dimorphism: an in silico and in vitro study
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/48a398096dfa4aa5b6b10ff2c34efb34
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Bacterial Quorum-Sensing Molecules as Promising Natural Inhibitors of Candida albicans Virulence Dimorphism: An In Silico and In Vitro Study

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