Antibiotics have drastically reduced the mortality associated with infectious diseases. Yet, their misuse and abuse have led to the development and spread of bacterial resistance. In addition, as antibiotics usually target essential bacterial pathways, they display a broad spectrum of action, thus lacking in specificity and damaging the host microbiota. The worldwide spread of antibiotic resistance and the severe side effects of the currently available antimicrobials on human health urge the identification and characterization of novel bacterial drug targets and anti-infectives.
The originality of our project is to provide an integrative and multidisciplinary strategy to thrive the development of effective first in class antibiotics, and to tackle the mechanisms underlying bacterial resistance by exploiting one innovative bacterial targets: the Mutation Frequency Decline protein (Mfd) and by promoting its inhibition by novel therapeutic molecules.
Mfd is a non-essential transcription repair coupling factor that is conserved in bacteria, but absent in eukaryotes. By conferring resistance to nitric oxide (NO), a major toxic component of the host innate immune system, Mfd activity enables the bacteria to overcome the host defense responses. Mfd Inhibitor hits displayed in vitro antimicrobial activity against at least one pathogenic species of the ESKAPE group.