NAD BIOSYNTHESIS: TOWARDS THE DISCOVERY OF NEW ANTIBACTERIAL AGENTS – NADIN

The discovery of antibiotics and their utilization in curing infections were among the most spectacular advances of the 20th century. However, it is widely recognized that microbes have the versatility and capability to develop resistance to various therapies. Although chemical modifications of existing drugs and the development of novel inhibitors against a handful of previously established targets have proven to be successful in the short term, it is evident that new drug targets need be explored to maintain and extend our antibacterial capabilities in the long run. The need of new targets is further exacerbated by the emergence of bacterial pathogens with increased resistance to existing antibiotics. The development of drugs acting on new targets is thus timely.
The NADIN project aims at identifying inhibitors of a new target, the quinolinate synthase enzyme (NadA), and testing their activity in vivo as antibacterial agents on two major pathogens, Helicobacter pylori and Mycobacterium leprae, organisms in which NadA is an essential enzyme. H. pylori is responsible for gastric cancers and M. leprae is the causative agent of leprosy. In these pathogens, NadA is an enzyme involved in the unique biosynthetic pathway of nicotinamide adenine dinucleotide (NAD), an essential cofactor in biology. Three strategies will be used to search for NadA inhibitors: (1) the design of synthetic molecules based on the first inhibitor that we made in 2012 and the use of recent NadA structural crystallographic data, (2) the virtual screening of compounds using molecular docking with two NadA X-ray structures as targets and (3) the use of high-throughput screening with NadA both in vitro and in vivo (i.e. on cultured bacteria). Promising molecules obtained from these approaches will be tested in vitro using purified NadA enzyme, then in vivo in H. pylori and M. leprae cultures and finally in mouse models infected with these pathogens. Chemical modifications will be used to improve the inhibitory effect of the found molecules. In summary, we plan to use chemical, biochemical, biological, structural and theoretical approaches in order to find antibacterial agents directed against a new target, the quinolinate synthase of H. pylori and M. leprae.