Discovery of Novel Serine Acetyltransferase Inhibitors through Virtual Screening and Structure–Activity Analysis

Numerous bacteria and actinomycetes rely on L-cysteine biosynthesis to enhance their tolerance to antibacterial agents and to sustain persistent infections, a phenomenon that contributes to the emergence of antimicrobial resistance—one of the most critical global public health challenges. As the enzymatic pathway responsible for L-cysteine production is absent in mammalian cells, it represents an attractive and selective target for therapeutic intervention. In this study, we describe the identification of a series of inhibitors targeting serine acetyltransferase (SAT) from Salmonella typhimurium, the enzyme responsible for catalyzing the rate-limiting step in L-cysteine biosynthesis. These inhibitors were discovered through a virtual screening campaign conducted on an in-house chemical library, which yielded seven structurally diverse hit compounds. Subsequent evaluation of analogues structurally related to hit compound 5—either sourced from the original library or generated through medicinal chemistry optimization—enabled the establishment of preliminary structure–activity relationships and led to a marked enhancement of inhibitory potency relative to the initial hit. Despite these improvements at the enzymatic level, the most advanced compound did not exhibit detectable antibacterial activity in a Gram-negative model organism, highlighting the need for further optimization and investigation.