O-Acetylserine sulfhydrylase (isoform A, OASS-A) is a pyridoxal-5’-phosphate-dependent enzyme responsible for cysteine biosynthesis in many pathological microorganisms. It is proposed that inhibition of OASS-A could represent a novel strategy to overcome bacterial resistance to antibiotics. A class of 2-substituted-cyclopropane-1-carboxylic acids were synthesized, based on structural determinants grasped by analyzing a group of synthetic pentapeptides known to efficiently bind OASS-A from Haemophilus influenzae (HiOASS-A). The cyclopropane derivatives were submitted to a binding affinity assay with HiOASS-A and three of them, with Kdiss in the low micromolar, showed higher affinity than the most active synthetic pentapeptide. Thus, in this communication we report the first example of potent small molecule inhibitors of HiOASS-A. In addition, a molecular modelling study suggested a possible inhibition mechanism, through which the new cyclopropane ligands block HiOASS-A. Noteworthy, the novel, small-sized, non-peptidic inhibitors retain the structural motifs of the bulky peptides, which are relevant for the enzyme inhibition.
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