Antibiotics have drastically reduced the mortality associated with infectious diseases. Yet, their effectiveness and easy access led to misuse and overuse, prompting bacteria to develop resistance. Currently, antibiotics are usually based on essential bacterial pathways, and therefore cover a broad spectrum of bacteria. There is however a high risk of resistance development, leading to a dramatic health issue and new medicines are thus urgently needed. A major challenge for efficient drug design is to find and characterize appropriate bacterial targets. Our PhD project focuses on an innovative bacterial target, the Mfd, Mutation Frequency Decline, protein. Mfd has been shown to both be able to confer bacterial resistance to nitric-oxide (NO), a major toxic component of the host innate immune system, and to act as an evolvability factor, as Mfd-driven mutagenesis accelerates the evolution of antimicrobial resistance. Accordingly, we patented the use of Mfd as a target for the discovery of new drugs (patent n°PCT/EP2017/060525) ⁽¹⁾. Recently we have identified NM102 molecule that inhibits Mfd by competing with ATP binding to its active site, and exclusively in the context of infection. 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 ⁽²⁾.

     This PhD project, circled to SDSV perimeter, aims to explore the conformational remodeling of Mfd using an integrative in silico/in crystallo approach. By analyzing the molecular mechanisms driving Mfd's structural transitions and interactions, the goal is to design molecules that inhibit its function, ultimately targeting Mfd as a therapeutic strategy. A particular focus of the PhD thesis will be on two key linkers within Mfd's core, hypothesized to play a crucial role in coordinating its structural rearrangements. This study is embedded in an interdisciplinary framework, incorporating structural biology and peptidomimetic design, with potential applications against ESKAPE pathogens.