The fight against bacteria is turning again into one of the greatest challenges faced by our
societies, especially with the spread of multi- and extensively-drug resistant bacteria. In particular, infections by the ESKAPE bacteria: E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter spp are increasingly associated with therapeutic dead-ends and
constitute the top WHO priority list of bacteria for which novel therapeutics are urgently needed. Despite this, the number of new molecules developed is really low and efforts must be made to fill this gap, especially towards Gram-negative pathogens. Identification and characterization of antibiotics with novel structures, targets and original mechanisms of action, associated with a low potential of resistance induction, is an emergency. Accordingly, this project focuses on an original and innovative bacterial target: the mutation frequency decline protein (Mfd) and its inhibition by novel molecules. Mfd is a non-essential transcription repair coupling factor ubiquitous in bacteria and absent in eukaryotes. Mfd recognizes RNA polymerase stalled atnon-coding lesions, uses energy from ATP hydrolysis to disrupt the transcription complex and stimulates DNA repair by recruiting components of the nucleotide excision repair machinery (1). Partner 1 discovered that
Mfd is critical for virulence and confers resistance to nitric oxide (NO) to Gram positive and negative bacteria (2). Innate immunity is the first line of defense against pathogens. During the inflammatory response, NO is secreted in large quantities and is a crucial antibacterial weapon (3). Mfd promotes resistance to the host NO response by stimulating repair of NO-dependent DNA damage (4). In addition, Mfd acts as an evolvability factor by promoting mutations thus enhancing the development of antibiotic resistance (5). The function of Mfd in the bacterial bypass of host immunity, its ubiquity in the prokaryotic world and its absence in higher eukaryotes all support the choice of this protein as an innovative bacterial target, patented by Partner 1
(WO/2017/191184).
Here, we propose a cutting-edge therapeutic approach in antibacterial treatment, by developing
molecules that do neither directly inhibit nor kill bacteria, but instead impede their ability to resist to the host immune response. Targeting this adaptation/virulence bacterial factor will allow to boost the immune system efficiency and to only focus on bacteria restricted to the inflammation site, thus reducing resistance and collateral damages. 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, thus fitting to the CE18 Biomedical Innovation of the ANR.