Vinyl sulfone core structure is known to rapidly undergo thiol-Michael addition under physiological condition. Due to the importance of cysteine-containing proteins in bacterial survival and pathogenesis of Gram-positive Staphylococcus aureus (S. aureus), we hypothesized that covalently modified the sulfhydryl group of cysteine could impact the bacterial surivial and pathogenesis. In this study, we constructed a focused library of vinyl sulfones and investigated the antibacterial activity against pathogenic bacteria, including global predominant methicillin-resistant Staphylococcus aureus (MRSA) USA300 strain SF8300. We discovered numbers of antibacterial vinyl sulfone. The nitrile-substituted vinyl phenyl sulfones exhibited the most potent antibacterial activity with MIC as low as 1.875 µg/ml against S. aureus ATCC 29213 and 3.75 µg/ml against MRSA USA300. Our study highlighted the potential of vinyl sulfones for S. aureus and MRSA therapeutics.