The present invention relates to the field of antimicrobial agents active against Staphylococcus aureus bacteria. In particular, the present invention relates to polypeptides comprising the CHAP domain of LysK endolysin, the M23 endopeptidase domain of lysostaphin, the cell wall binding domain (CBD) of ALE-1, and a further peptide selected from the group consisting of an antimicrobial peptide, an amphipathic peptide, a cationic peptide, a hydrophobic peptide, a sushi peptide and a defensin. In addition, the present invention relates to nucleic acids encoding such polypeptides, vectors comprising such nucleic acids, and corresponding host cells, compositions and devices. Finally, the present invention relates to applications of the inventive polypeptides, in particular in the pharmaceutical field.