Benzotriazole derivatives as alternate O-acetylserine sulfhydrylase substrates to impair cysteine biosynthesis in Gram-negative bacteria

Cysteine biosynthetic pathway, unique to bacteria and absent in the human host, represents a relevant reservoir of potential antimicrobial targets. Cysteine, in fact, is involved in redox homeostasis and prone to the production of reactive oxygen species, and altering its metabolic equilibrium provokes severe consequences on bacterial fitness and antibiotic response. Here, we developed a library of benzotriazole-derived compounds targeting O-acetylserine sulfhydrylase (OASS) - the enzyme responsible for cysteine synthesis in most pathogenic bacteria - which act as alternate OASS substrates that can impair cysteine production. The library was tested on three clinically relevant Gram-negative species, and the three most promising candidates, upon the validation of their mechanism of action in vitro, were demonstrated to have adjuvant effect in combination with selected approved antibiotics. While further optimization is required before their application, these molecules might find application as adjuvants of the antibiotic therapy and help to preserve existing drugs.