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ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system

Antivirulence strategy has been developed as a nontraditional therapy which would engender a lower evolutionary pressure toward the development of antimicrobial resistance. However, the majority of the antivirulence agents currently in development could not meet clinical needs due to their narrow an...

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Autores principales: Zhang, Youwen, Dong, Limin, Sun, Lang, Hu, Xinxin, Wang, Xiukun, Nie, Tongying, Li, Xue, Wang, Penghe, Pang, Pengbo, Pang, Jing, Lu, Xi, Yao, Kaihu, You, Xuefu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813848/
https://www.ncbi.nlm.nih.gov/pubmed/36619997
http://dx.doi.org/10.3389/fmicb.2022.980217
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author Zhang, Youwen
Dong, Limin
Sun, Lang
Hu, Xinxin
Wang, Xiukun
Nie, Tongying
Li, Xue
Wang, Penghe
Pang, Pengbo
Pang, Jing
Lu, Xi
Yao, Kaihu
You, Xuefu
author_facet Zhang, Youwen
Dong, Limin
Sun, Lang
Hu, Xinxin
Wang, Xiukun
Nie, Tongying
Li, Xue
Wang, Penghe
Pang, Pengbo
Pang, Jing
Lu, Xi
Yao, Kaihu
You, Xuefu
author_sort Zhang, Youwen
collection PubMed
description Antivirulence strategy has been developed as a nontraditional therapy which would engender a lower evolutionary pressure toward the development of antimicrobial resistance. However, the majority of the antivirulence agents currently in development could not meet clinical needs due to their narrow antibacterial spectrum and limited indications. Therefore, our main purpose is to develop broad-spectrum antivirulence agents that could target on both Gram-positive and Gram-negative pathogens. We discovered ML364, a novel scaffold compound, could inhibit the productions of both pyocyanin of Pseudomonas aeruginosa and staphyloxanthin of Staphylococcus aureus. Further transcriptome sequencing and enrichment analysis showed that the quorum sensing (QS) system of pathogens was mainly disrupted by ML364 treatment. To date, autoinducer-2 (AI-2) of the QS system is the only non-species-specific signaling molecule that responsible for the cross-talk between Gram-negative and Gram-positive species. And further investigation showed that ML364 treatment could significantly inhibit the sensing of AI-2 or its nonborated form DPD signaling in Vibrio campbellii MM32 and attenuate the biofilm formation across multi-species pathogens including Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. The results of molecular docking and MM/GBSA free energy prediction showed that ML364 might have higher affinity with the receptors of DPD/AI-2, when compared with DPD molecule. Finally, the in vivo study showed that ML364 could significantly improve the survival rates of systemically infected mice and attenuate bacterial loads in the organs of mice. Overall, ML364 might interfere with AI-2 quorum sensing system to exert broad-spectrum antivirulence effect both in vitro and in vivo.
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spelling pubmed-98138482023-01-06 ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system Zhang, Youwen Dong, Limin Sun, Lang Hu, Xinxin Wang, Xiukun Nie, Tongying Li, Xue Wang, Penghe Pang, Pengbo Pang, Jing Lu, Xi Yao, Kaihu You, Xuefu Front Microbiol Microbiology Antivirulence strategy has been developed as a nontraditional therapy which would engender a lower evolutionary pressure toward the development of antimicrobial resistance. However, the majority of the antivirulence agents currently in development could not meet clinical needs due to their narrow antibacterial spectrum and limited indications. Therefore, our main purpose is to develop broad-spectrum antivirulence agents that could target on both Gram-positive and Gram-negative pathogens. We discovered ML364, a novel scaffold compound, could inhibit the productions of both pyocyanin of Pseudomonas aeruginosa and staphyloxanthin of Staphylococcus aureus. Further transcriptome sequencing and enrichment analysis showed that the quorum sensing (QS) system of pathogens was mainly disrupted by ML364 treatment. To date, autoinducer-2 (AI-2) of the QS system is the only non-species-specific signaling molecule that responsible for the cross-talk between Gram-negative and Gram-positive species. And further investigation showed that ML364 treatment could significantly inhibit the sensing of AI-2 or its nonborated form DPD signaling in Vibrio campbellii MM32 and attenuate the biofilm formation across multi-species pathogens including Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. The results of molecular docking and MM/GBSA free energy prediction showed that ML364 might have higher affinity with the receptors of DPD/AI-2, when compared with DPD molecule. Finally, the in vivo study showed that ML364 could significantly improve the survival rates of systemically infected mice and attenuate bacterial loads in the organs of mice. Overall, ML364 might interfere with AI-2 quorum sensing system to exert broad-spectrum antivirulence effect both in vitro and in vivo. Frontiers Media S.A. 2022-12-22 /pmc/articles/PMC9813848/ /pubmed/36619997 http://dx.doi.org/10.3389/fmicb.2022.980217 Text en Copyright © 2022 Zhang, Dong, Sun, Hu, Wang, Nie, Li, Wang, Pang, Pang, Lu, Yao and You. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Zhang, Youwen
Dong, Limin
Sun, Lang
Hu, Xinxin
Wang, Xiukun
Nie, Tongying
Li, Xue
Wang, Penghe
Pang, Pengbo
Pang, Jing
Lu, Xi
Yao, Kaihu
You, Xuefu
ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system
title ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system
title_full ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system
title_fullStr ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system
title_full_unstemmed ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system
title_short ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system
title_sort ml364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813848/
https://www.ncbi.nlm.nih.gov/pubmed/36619997
http://dx.doi.org/10.3389/fmicb.2022.980217
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