The rise of a global antibiotic resistance crisis is severely exacerbated by the lack of new drug development in the field of antibiotics. The discovery of a novel bacterial pathway is paramount in the fight to combat this urgent situation. We have identified N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) as a promising bacterial enzyme target in the lysine biosynthetic pathway of all Gram-negative and most Gram-positive bacteria. DapE is a di-zinc metalloenzyme that catalyzes the hydrolysis of N-succinyl-L,L-diaminopimelic acid (L,L-SDAP) to succinate and L,L-diaminopimelic acid (L,L-DAP), and in addition to the synthesis of lysine, it is key to the production of meso-diaminopimelic acid (m-DAP), which is used in bacterial cell wall synthesis. The absence of the DapE biosynthetic pathway in mammals suggests that inhibitors of DapE should serve as broad-spectrum antibiotics with selective toxicity toward bacteria without mechanism-based toxicity in humans. We have studied the substantial conformational change during enzymatic hydrolysis by DapE and have identified a number of potential inhibitors for this enzyme in our laboratory. To further optimize inhibitors as potential antibiotics, it is important to fully understand the mechanism of action in the catalytic site. Despite computational and experimental work done on the active site and catalytic mechanism by us and others, one important question remains: is the zinc-bridging oxygen in the active site part of a water or hydroxide? On a foundation of experimental, computational, and X-ray crystallographic work, we have employed quantum mechanical gas and liquid phase optimizations of the DapE active site and compared the results to experimental data to make conclusions about the identity of the zinc-binding oxygen.

Identifying the zinc-bridging oxygen in the active site of DAPE using computational chemistry

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