New antibacterial compounds targeting NAD kinase – ANAKIN (Anti-NAd-Kinase)

The synthetic route to our bactericidal compounds will be optimized to provide us with molecules for in vitro and in vivo assays. The binding mode of inhibitors for the target, as determined by X-ray crystallography, shall guide the design of an optimal 'lead' compound. The newly synthesized analogues will be studied for their inhibitory effect in vitro on purified enzymes and for the most potent compounds on bacteria growth in culture media. The mechanism of action will be validated in vitro by over expression of NAD kinase. Finally, compounds showing the highest biological activity in vitro will be tested for their antibacterial potential in murine models of infection.

We successfuly scaled up the synthesis of our compounds and started the optimization of their properties. Some compounds have antibacterial activity against S. aureus in vitro. In parallel, we set up a therapeutic protocol based on known antibiotics in a mouse model of S. aureus infection to monitor the antibacterial potential of best compounds.

Our project should lead to the identification of a new class of antibiotics and validation of NAD kinase as a target for the development of antibacterials.

The original approach used to identify our first compounds with bactericidal activity in vitro against Staphylococcus aureus was published in Structure (Gelin et al., 2012, 20, 1107). This work was also outlined in ERCF Hightlights 2012 (http://www.esrf.eu/UsersAndScience/Publications/Highlights/)

Driven by the appearance of antibiotic-resistant bacterial pathogens, there is an ever-pressing need for new antibiotics. Complete genome sequencing of many microbial species has highlighted, during the last decade, a large number of potential molecular targets. Among them, nicotinamide adenosine dinucleotide kinase (NAD kinase) is a ubiquitous enzyme involved in the last step of NADP biosynthesis. NAD(P) biosynthesis is a promising, albeit relatively unexplored, target pathway for the development of novel antimicrobial agents.

Thanks to significant functional and structural characterization, bacterial NAD kinases can be regarded as novel and attractive for the development of selective antibacterial drugs. We have recently identified following a « target-guided synthesis » approach, a series of micromolar inhibitors of NAD kinase. Some showed promising bactericidal activities on Staphylococcus aureus. A patent was deposited protecting a first family of nucleoside derivatives.

In this project, we aim to demonstrate the antibacterial activity of our compounds in vivo using a mouse model of staphylococcal infection. We will also confirmed in vitro the mechanism of action and validate NAD kinase as the actual target of these new antibacterial series. In parallel, biological activity will be improved by chemical optimization of our current hits. All together these data will strengthen our results recently patented (EP 10290679.9).