Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogens
Summary: Antibiotic resistance is a major threat to human health and new drugs are urgently needed. Ideally, these drugs should have several cellular targets in pathogens, decreasing the risk of resistance development. We show here that two natural ribosomally synthesized lasso peptides (LPs), svice...
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Elsevier
2025-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225001828 |
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| author | Abdelhakim Boudrioua Benjamin Baëtz Solenn Desmadril Christophe Goulard Anne-Claire Groo Carine Lombard Sabrina Gueulle Marie Marugan Aurélie Malzert-Fréon Axel Hartke Yanyan Li Caroline Giraud |
| author_facet | Abdelhakim Boudrioua Benjamin Baëtz Solenn Desmadril Christophe Goulard Anne-Claire Groo Carine Lombard Sabrina Gueulle Marie Marugan Aurélie Malzert-Fréon Axel Hartke Yanyan Li Caroline Giraud |
| author_sort | Abdelhakim Boudrioua |
| collection | DOAJ |
| description | Summary: Antibiotic resistance is a major threat to human health and new drugs are urgently needed. Ideally, these drugs should have several cellular targets in pathogens, decreasing the risk of resistance development. We show here that two natural ribosomally synthesized lasso peptides (LPs), sviceucin and siamycin I, (1) abolish bacterial virulence of pathogenic enterococci, (2) restore vancomycin clinical susceptibility of vancomycin-resistant (VR) enterococci in vitro and in a surrogate animal model, and (3) re-sensitize VR Staphylococcus aureus. Mode of action (MoA) analyses showed that they do so by inhibiting the histidine kinases (HKs) FsrC and VanS controlling these phenotypes. Strains resistant to the vancomycin/LP combination were difficult to obtain, and were still fully susceptible to the anti-virulence effect of the LPs, highlighting the advantage of multiple targets. Together with the highly sought-after MoA as HK inhibitors, such properties make these lasso peptides promising candidates for the development of next generation antibiotics. |
| format | Article |
| id | doaj-art-211114420d1648aca0f2eb0caf3f6a95 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-211114420d1648aca0f2eb0caf3f6a952025-08-20T02:43:16ZengElsevieriScience2589-00422025-03-0128311192210.1016/j.isci.2025.111922Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogensAbdelhakim Boudrioua0Benjamin Baëtz1Solenn Desmadril2Christophe Goulard3Anne-Claire Groo4Carine Lombard5Sabrina Gueulle6Marie Marugan7Aurélie Malzert-Fréon8Axel Hartke9Yanyan Li10Caroline Giraud11Université de Caen Normandie, CBSA UR4312, F-14000 Caen, FranceUniversité de Caen Normandie, CBSA UR4312, F-14000 Caen, FranceUniversité de Caen Normandie, CBSA UR4312, F-14000 Caen, FranceUnit Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-Muséum National d’Histoire Naturelle (MNHN), 75005 Paris, FranceNormandie University, Unicaen, CERMN, 14000 Caen, FranceUnit Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-Muséum National d’Histoire Naturelle (MNHN), 75005 Paris, FranceUniversité de Caen Normandie, CBSA UR4312, F-14000 Caen, FranceUnit Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-Muséum National d’Histoire Naturelle (MNHN), 75005 Paris, FranceNormandie University, Unicaen, CERMN, 14000 Caen, FranceUniversité de Caen Normandie, CBSA UR4312, F-14000 Caen, FranceUnit Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-Muséum National d’Histoire Naturelle (MNHN), 75005 Paris, France; Corresponding authorUniversité de Caen Normandie, CBSA UR4312, F-14000 Caen, France; Corresponding authorSummary: Antibiotic resistance is a major threat to human health and new drugs are urgently needed. Ideally, these drugs should have several cellular targets in pathogens, decreasing the risk of resistance development. We show here that two natural ribosomally synthesized lasso peptides (LPs), sviceucin and siamycin I, (1) abolish bacterial virulence of pathogenic enterococci, (2) restore vancomycin clinical susceptibility of vancomycin-resistant (VR) enterococci in vitro and in a surrogate animal model, and (3) re-sensitize VR Staphylococcus aureus. Mode of action (MoA) analyses showed that they do so by inhibiting the histidine kinases (HKs) FsrC and VanS controlling these phenotypes. Strains resistant to the vancomycin/LP combination were difficult to obtain, and were still fully susceptible to the anti-virulence effect of the LPs, highlighting the advantage of multiple targets. Together with the highly sought-after MoA as HK inhibitors, such properties make these lasso peptides promising candidates for the development of next generation antibiotics.http://www.sciencedirect.com/science/article/pii/S2589004225001828DrugsBiochemistryPeptidesMedical Microbiology |
| spellingShingle | Abdelhakim Boudrioua Benjamin Baëtz Solenn Desmadril Christophe Goulard Anne-Claire Groo Carine Lombard Sabrina Gueulle Marie Marugan Aurélie Malzert-Fréon Axel Hartke Yanyan Li Caroline Giraud Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogens iScience Drugs Biochemistry Peptides Medical Microbiology |
| title | Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogens |
| title_full | Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogens |
| title_fullStr | Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogens |
| title_full_unstemmed | Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogens |
| title_short | Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogens |
| title_sort | lasso peptides sviceucin and siamycin i exhibit anti virulence activity and restore vancomycin effectiveness in vancomycin resistant pathogens |
| topic | Drugs Biochemistry Peptides Medical Microbiology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225001828 |
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