An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens
Abstract The increasing incidence of antibiotic resistance and the decline in the discovery of novel antibiotics have resulted in a global health crisis, particularly, for the treatment of infections caused by Gram-negative bacteria, for which therapeutic dead-ends are alarming. Here, we identify an...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58282-8 |
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| author | Seav-Ly Tran Lucie Lebreuilly Delphine Cormontagne Samantha Samson Thu Ba Tô Marie Stosskopf Rozenn Dervyn Anne Grießhammer Jacobo de la Cuesta-Zuluaga Lisa Maier Thierry Naas Simona Mura Didier Rognan Julien Nicolas Gwenaëlle André Nalini Ramarao |
| author_facet | Seav-Ly Tran Lucie Lebreuilly Delphine Cormontagne Samantha Samson Thu Ba Tô Marie Stosskopf Rozenn Dervyn Anne Grießhammer Jacobo de la Cuesta-Zuluaga Lisa Maier Thierry Naas Simona Mura Didier Rognan Julien Nicolas Gwenaëlle André Nalini Ramarao |
| author_sort | Seav-Ly Tran |
| collection | DOAJ |
| description | Abstract The increasing incidence of antibiotic resistance and the decline in the discovery of novel antibiotics have resulted in a global health crisis, particularly, for the treatment of infections caused by Gram-negative bacteria, for which therapeutic dead-ends are alarming. Here, we identify and characterize a molecule, NM102, that displays antimicrobial activity exclusively in the context of infection. NM102 inhibits the activity of the non-essential Mutation Frequency Decline (Mfd) protein by competing with ATP binding to its active site. Inhibition of Mfd by NM102 sensitizes pathogenic bacteria to the host immune response and blocks infections caused by the clinically-relevant bacteria Klebsiella pneumoniae and Pseudomonas aeruginosa, without inducing host toxicity. Finally, NM102 inhibits the mutation and evolvability function of Mfd, thus reducing the bacterial capacity to develop antimicrobial resistance. These data provide a potential roadmap for the development of drugs to combat antimicrobial resistance. |
| format | Article |
| id | doaj-art-9063f78f3dca4da7ab0819da0309ed4b |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9063f78f3dca4da7ab0819da0309ed4b2025-08-20T02:55:23ZengNature PortfolioNature Communications2041-17232025-04-0116111910.1038/s41467-025-58282-8An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogensSeav-Ly Tran0Lucie Lebreuilly1Delphine Cormontagne2Samantha Samson3Thu Ba Tô4Marie Stosskopf5Rozenn Dervyn6Anne Grießhammer7Jacobo de la Cuesta-Zuluaga8Lisa Maier9Thierry Naas10Simona Mura11Didier Rognan12Julien Nicolas13Gwenaëlle André14Nalini Ramarao15Université Paris-Saclay, INRAE, Micalis InstituteUniversité Paris-Saclay, INRAE, Micalis InstituteUniversité Paris-Saclay, INRAE, Micalis InstituteUniversité Paris-Saclay, INRAE, Micalis InstituteUniversité Paris-Saclay, INRAE, Micalis InstituteUniversité Paris-Saclay, INRAE, Micalis InstituteUniversité Paris-Saclay, INRAE, Micalis InstituteInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenTeam ReSIST, INSERM U1184, School of Medicine Université Paris-Saclay, LabEx LERMIT, Assistance Publique/Hôpitaux de Paris, French NRC for Carbapenemase-Producing Enterobacterales. Bicêtre HospitalUniversité Paris-Saclay, CNRS, Institut Galien Paris-SaclayUniversité de Strasbourg, CNRS, UMR 7200 LiTUniversité Paris-Saclay, CNRS, Institut Galien Paris-SaclayUniversité Paris-Saclay, INRAE, MaIAGEUniversité Paris-Saclay, INRAE, Micalis InstituteAbstract The increasing incidence of antibiotic resistance and the decline in the discovery of novel antibiotics have resulted in a global health crisis, particularly, for the treatment of infections caused by Gram-negative bacteria, for which therapeutic dead-ends are alarming. Here, we identify and characterize a molecule, NM102, that displays antimicrobial activity exclusively in the context of infection. NM102 inhibits the activity of the non-essential Mutation Frequency Decline (Mfd) protein by competing with ATP binding to its active site. Inhibition of Mfd by NM102 sensitizes pathogenic bacteria to the host immune response and blocks infections caused by the clinically-relevant bacteria Klebsiella pneumoniae and Pseudomonas aeruginosa, without inducing host toxicity. Finally, NM102 inhibits the mutation and evolvability function of Mfd, thus reducing the bacterial capacity to develop antimicrobial resistance. These data provide a potential roadmap for the development of drugs to combat antimicrobial resistance.https://doi.org/10.1038/s41467-025-58282-8 |
| spellingShingle | Seav-Ly Tran Lucie Lebreuilly Delphine Cormontagne Samantha Samson Thu Ba Tô Marie Stosskopf Rozenn Dervyn Anne Grießhammer Jacobo de la Cuesta-Zuluaga Lisa Maier Thierry Naas Simona Mura Didier Rognan Julien Nicolas Gwenaëlle André Nalini Ramarao An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens Nature Communications |
| title | An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens |
| title_full | An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens |
| title_fullStr | An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens |
| title_full_unstemmed | An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens |
| title_short | An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens |
| title_sort | anti virulence drug targeting the evolvability protein mfd protects against infections with antimicrobial resistant eskape pathogens |
| url | https://doi.org/10.1038/s41467-025-58282-8 |
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