The discovery of antibiotics and their use in the treatment of infections was one of the most spectacular medical breakthroughs of the 20th century. However, the massive and sometimes excessive use of antibiotics is gradually making bacteria resistant to them. Bacterial resistance to antibiotics is prompting researchers to find new antibacterial substances and targets. The biosynthesis of nicotinamide adenine dinucleotide (NAD), an essential cofactor in biology, is an interesting metabolic pathway for the development of new antibacterial agents. Indeed, one of the reaction intermediates of this biosynthetic pathway, quinolinic acid, is synthesized differently in prokaryotes and eukaryotes. In most eukaryotes, it is produced via the degradation of L-tryptophan, whereas in opportunistic and pathogenic bacteria, as well as in plants, it is synthesized from L-aspartate under the successive action of two enzymes: L-aspartate oxidase (NadB) and quinolinate synthase (NadA). This makes quinolinate synthase and L-aspartate oxidase particularly attractive targets for the development of new antibacterial agents. To date, no quinolinate synthase inhibitors have been demonstrated either in vitro orin vivo. NadA is a universal metalloprotein with an essential Fe4S4 center. The catalytic mechanism of the reaction catalyzed by quinolinate synthase is still poorly understood, as is the role of the FeS center in catalysis.
Understanding the mechanism of the reaction catalyzed by quinolinate synthase is therefore a real challenge in biological chemistry. In the course of the seminar, we will first outline the different stages of the NAD biosynthetic pathway in eukaryotes and prokaryotes, with a particular focus on the stage in which the NadA quinolinate synthase is involved. Our recent work on quinolinate synthase is then discussed, including the use of a molecule as a mechanistic probe of the reaction catalyzed by NadA, and as a potential new antibacterial agent with a novel mode of action.
