Myricetin Potentiates Antibiotics Against Resistant <i>Pseudomonas aeruginosa</i> by Disrupting Biofilm Formation and Inhibiting Motility Through FimX-Mediated c-di-GMP Signaling Interference
<i>Pseudomonas aeruginosa</i> biofilm formation is critical to antibiotic resistance and persistence. Targeting cyclic di-GMP (c-di-GMP) signaling, a master biofilm formation and virulence regulator, presents a promising strategy to combat resistant bacterial infections. Myricetin, a nat...
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2025-07-01
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| author | Derong Zeng Fangfang Jiao Yuqi Yang Shuai Dou Jiahua Yu Xiang Yu Yongqiang Zhou Juan Xue Xue Li Hongliang Duan Yan Zhang Jingjing Guo Wude Yang |
| author_facet | Derong Zeng Fangfang Jiao Yuqi Yang Shuai Dou Jiahua Yu Xiang Yu Yongqiang Zhou Juan Xue Xue Li Hongliang Duan Yan Zhang Jingjing Guo Wude Yang |
| author_sort | Derong Zeng |
| collection | DOAJ |
| description | <i>Pseudomonas aeruginosa</i> biofilm formation is critical to antibiotic resistance and persistence. Targeting cyclic di-GMP (c-di-GMP) signaling, a master biofilm formation and virulence regulator, presents a promising strategy to combat resistant bacterial infections. Myricetin, a natural polyphenolic flavonoid with documented antimicrobial and anti-biofilm activities, may enhance antibiotic efficacy against <i>Pseudomonas aeruginosa</i>. This study evaluated the synergistic effects of myricetin combined with azithromycin, ciprofloxacin, or cefdinir against both standard and drug-resistant <i>Pseudomonas aeruginosa</i> strains. Antibacterial activity, biofilm disruption, and motility inhibition were experimentally assessed, while molecular dynamic (MD) simulations elucidated myricetin’s molecular mechanism of action. Our results suggested that myricetin synergistically potentiated all three antibiotics, reducing c-di-GMP synthesis by 28% (azithromycin), 57% (ciprofloxacin), and 30% (cefdinir). It enhanced bactericidal effects, suppressed biofilm formation, and impaired swimming, swarming, and twitching motility. Computational analyses revealed that myricetin binds allosterically to FimX very well, a key regulator in the c-di-GMP signaling pathway. Hence, myricetin may act as a c-di-GMP inhibitor, reversing biofilm-mediated resistance in <i>Pseudomonas aeruginosa</i> and augmenting antibiotic efficacy. This integrated experimental and computational approach provides a framework for developing anti-virulence and antibiotic combination therapies against recalcitrant Gram-negative pathogens. |
| format | Article |
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| issn | 2079-7737 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| series | Biology |
| spelling | doaj-art-afad85f1d94e475f95d697c067b2dd6f2025-07-25T13:15:12ZengMDPI AGBiology2079-77372025-07-0114785910.3390/biology14070859Myricetin Potentiates Antibiotics Against Resistant <i>Pseudomonas aeruginosa</i> by Disrupting Biofilm Formation and Inhibiting Motility Through FimX-Mediated c-di-GMP Signaling InterferenceDerong Zeng0Fangfang Jiao1Yuqi Yang2Shuai Dou3Jiahua Yu4Xiang Yu5Yongqiang Zhou6Juan Xue7Xue Li8Hongliang Duan9Yan Zhang10Jingjing Guo11Wude Yang12College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaCentre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, ChinaSchool of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaCollege of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaCollege of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaCollege of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaCollege of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaCollege of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaThe Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaCentre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, ChinaCollege of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, ChinaCentre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, ChinaCollege of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China<i>Pseudomonas aeruginosa</i> biofilm formation is critical to antibiotic resistance and persistence. Targeting cyclic di-GMP (c-di-GMP) signaling, a master biofilm formation and virulence regulator, presents a promising strategy to combat resistant bacterial infections. Myricetin, a natural polyphenolic flavonoid with documented antimicrobial and anti-biofilm activities, may enhance antibiotic efficacy against <i>Pseudomonas aeruginosa</i>. This study evaluated the synergistic effects of myricetin combined with azithromycin, ciprofloxacin, or cefdinir against both standard and drug-resistant <i>Pseudomonas aeruginosa</i> strains. Antibacterial activity, biofilm disruption, and motility inhibition were experimentally assessed, while molecular dynamic (MD) simulations elucidated myricetin’s molecular mechanism of action. Our results suggested that myricetin synergistically potentiated all three antibiotics, reducing c-di-GMP synthesis by 28% (azithromycin), 57% (ciprofloxacin), and 30% (cefdinir). It enhanced bactericidal effects, suppressed biofilm formation, and impaired swimming, swarming, and twitching motility. Computational analyses revealed that myricetin binds allosterically to FimX very well, a key regulator in the c-di-GMP signaling pathway. Hence, myricetin may act as a c-di-GMP inhibitor, reversing biofilm-mediated resistance in <i>Pseudomonas aeruginosa</i> and augmenting antibiotic efficacy. This integrated experimental and computational approach provides a framework for developing anti-virulence and antibiotic combination therapies against recalcitrant Gram-negative pathogens.https://www.mdpi.com/2079-7737/14/7/859<i>Pseudomonas aeruginosa</i>antibiotic resistancebiofilmc-di-GMPFimXmyricetin |
| spellingShingle | Derong Zeng Fangfang Jiao Yuqi Yang Shuai Dou Jiahua Yu Xiang Yu Yongqiang Zhou Juan Xue Xue Li Hongliang Duan Yan Zhang Jingjing Guo Wude Yang Myricetin Potentiates Antibiotics Against Resistant <i>Pseudomonas aeruginosa</i> by Disrupting Biofilm Formation and Inhibiting Motility Through FimX-Mediated c-di-GMP Signaling Interference Biology <i>Pseudomonas aeruginosa</i> antibiotic resistance biofilm c-di-GMP FimX myricetin |
| title | Myricetin Potentiates Antibiotics Against Resistant <i>Pseudomonas aeruginosa</i> by Disrupting Biofilm Formation and Inhibiting Motility Through FimX-Mediated c-di-GMP Signaling Interference |
| title_full | Myricetin Potentiates Antibiotics Against Resistant <i>Pseudomonas aeruginosa</i> by Disrupting Biofilm Formation and Inhibiting Motility Through FimX-Mediated c-di-GMP Signaling Interference |
| title_fullStr | Myricetin Potentiates Antibiotics Against Resistant <i>Pseudomonas aeruginosa</i> by Disrupting Biofilm Formation and Inhibiting Motility Through FimX-Mediated c-di-GMP Signaling Interference |
| title_full_unstemmed | Myricetin Potentiates Antibiotics Against Resistant <i>Pseudomonas aeruginosa</i> by Disrupting Biofilm Formation and Inhibiting Motility Through FimX-Mediated c-di-GMP Signaling Interference |
| title_short | Myricetin Potentiates Antibiotics Against Resistant <i>Pseudomonas aeruginosa</i> by Disrupting Biofilm Formation and Inhibiting Motility Through FimX-Mediated c-di-GMP Signaling Interference |
| title_sort | myricetin potentiates antibiotics against resistant i pseudomonas aeruginosa i by disrupting biofilm formation and inhibiting motility through fimx mediated c di gmp signaling interference |
| topic | <i>Pseudomonas aeruginosa</i> antibiotic resistance biofilm c-di-GMP FimX myricetin |
| url | https://www.mdpi.com/2079-7737/14/7/859 |
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