An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens

Seav-Ly Tran, Lucie Lebreuilly, Delphine Cormontagne, Samantha Samson, Thu Ba Tô, Marie Stosskopf, Rozenn Dervyn, Anne Grießhammer, Jacobo Cuesta-Zuluaga, Lisa Maier, Thierry Naas, Simona Mura, Didier Rognan, Julien Nicolas, Gwenaëlle André and Nalini Ramarao ()
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Seav-Ly Tran: Université Paris-Saclay, INRAE, Micalis Institute
Lucie Lebreuilly: Université Paris-Saclay, INRAE, Micalis Institute
Delphine Cormontagne: Université Paris-Saclay, INRAE, Micalis Institute
Samantha Samson: Université Paris-Saclay, INRAE, Micalis Institute
Thu Ba Tô: Université Paris-Saclay, INRAE, Micalis Institute
Marie Stosskopf: Université Paris-Saclay, INRAE, Micalis Institute
Rozenn Dervyn: Université Paris-Saclay, INRAE, Micalis Institute
Anne Grießhammer: University of Tübingen
Jacobo Cuesta-Zuluaga: University of Tübingen
Lisa Maier: University of Tübingen
Thierry Naas: INSERM U1184, School of Medicine Université Paris-Saclay, LabEx LERMIT, Assistance Publique/Hôpitaux de Paris, French NRC for Carbapenemase-Producing Enterobacterales. Bicêtre Hospital
Simona Mura: Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay
Didier Rognan: Université de Strasbourg, CNRS, UMR 7200 LiT
Julien Nicolas: Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay
Gwenaëlle André: Université Paris-Saclay, INRAE, MaIAGE
Nalini Ramarao: Université Paris-Saclay, INRAE, Micalis Institute

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58282-8

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