New antimicrobials against ESKAPE pathogens to fight nitric oxide stress resistance – NO-ESKAPE

Antibiotic resistance is a dramatic health challenge and development of new antibiotics efficient against Gram-negative bacteria of the ESKAPE group is an emergency. In this project, we propose the development of effective first-in-class antibiotics to tackle bacterial resistance by acting on a novel bacterial target, the Mutation Frequency Decline protein (Mfd), and by promoting its inhibition by novel therapeutic molecules.
Mfd is a non-essential transcription repair coupling factor conserved in bacteria and absent in eukaryotes. Mfd enables the bacteria to overcome the host defense responses, by conferring resistance to nitric oxide, a major toxic component of the innate immune system. We have identified selective Mfd inhibitors and demonstrated their efficacy against Gram-negative bacteria. Herein, we will optimize these molecules and test their efficacy against bacteria of the ESKAPE group. We will also tackle their pharmacologically challenging properties and develop optimal nanoparticle formulations to ensure their efficient delivery. The originality of our project from a therapeutic perspective is the optimization of compounds that, instead of killing the bacteria responsible for the infection, will block their pathogenic pathways. Targeting Mfd’s function will allow to boost the immune system efficiency and to only focus on bacteria restricted to the inflammation site, thus reducing resistance. This translational project aims to deliver a drug candidate with a solid pre-clinical proof of concept of innocuity to the host and broad range efficacy. As result, a strong therapeutic innovation able to bring an effective healthcare solution to the out-of-control rise of antibiotic resistance will be provided. The complementary and multidisciplinary consortium has already successfully worked together and obtained significant preliminary data, which allow us to be confident about the ultimate success on our challenging project.