Integrated In Silico - In Vitro Study Investigating Dipeptides as Chorismate Synthase Modulators: Spotlight on Its...

Campylobacter jejuni is a widespread foodborne pathogen causing campylobacteriosis, a disease leading to diarrhea, fever, and gastroenteritis, able to adapt to many niches. Here, we present a hybrid in silico/in vitro study investigating the modulation of C. jejuni chorismate synthase by peptides. This enzyme belongs to the shikimate pathway, and it is an interesting target for selective growth modulation, being crucial for bacteria but not present in animals. To account for the identification of "natural" modulators, a library of 400 dipeptides is screened in silico through docking and molecular dynamics simulations to identify possible inhibiting sequences. The dipeptide glutamate-aspartate (ED) stood out, emulating the pharmacophoric fingerprint and interaction of the enzyme's natural substrate. Serendipitously, in vitro trials revealed ED as an activity enhancer. Considering the growth of C. jejuni in protein-rich matrices, this outlined a possibly relevant matrix-dependent effect worthy of dedicated investigations. The underpinning mechanisms are computationally investigated, describing possible ED-dependent effects on substrate/product turnover and enzyme structural stability. This study deepened the understanding of chorismate synthase and opened new directions in designing food-grade peptide-based modulators. This may provide ground to improve controlling bacterial growth in diverse contexts, including food safety and environmental/agricultural hygiene.