Inhibition of Nicotinamidase Impacts Growth, Development, and Lifespan of Drosophila melanogaster and Myzus persicae

Nicotinamidase (Naam), which is essential for insect NAD synthesis but absent in mammals, represents a potential pesticide target. Virtual screening identified 1-[4-(trifluoromethyl)-3-pyridinyl]-ethanone (4-TFPE) as a potent inhibitor of Myzus persicae (IC50 = 4.156 μM) and Drosophila melanogaster (IC50 = 2.855 μM) Naam. While 4-TFPE reduced pupal weight, development, and longevity in both species, it showed no lethal toxicity. Crucially, Naam expression was upregulated by nicotinamide accumulation, revealing a feedback regulation mechanism that compromises its pesticidal potential. Furthermore, Flumetnicam’s neurotoxic effects were found to be Naam-independent. These findings highlight how target compensation mechanisms can undermine pesticide development focused on single metabolic enzymes, suggesting the need for multitarget strategies.