Novel treatment strategies are needed to control infections by antibiotic-resistant bacteria. One way to achieve this is to improve the activity of our immune system via therapeutic antibodies. Human immune protection against invading Gram-negative bacteria critically depends on blood components designated as “the complement system” that directly kill bacterial cells by formation of lytic pores (membrane attack complexes, MACs). Since complement can be specifically turned on via antibodies, design of complement-activating antibodies is an attractive route for novel anti-bacterial therapies. Identification of potent anti-bacterial antibodies, however, is hampered by our lack of insights into molecular events underlying antibody-dependent complement activation on bacteria. In preliminary experiments we identified important functional differences between immunoglobulin isotypes in the killing of Gram-negative bacteria. While IgG and IgM antibodies have equal complement-activating capacity on Gram-positive bacteria, IgM is far superior in triggering MAC- mediated killing of Gram-negatives. This was not only evident when we compared polyclonal human IgG/IgM antibodies but also for comparison of monoclonal IgM and IgGs that have the exact same Fab sequence. Since these insights could be key to the development of potent antibody therapies against Gram-negative bacteria, we here aim to unravel why IgM antibodies have superior killing activity. Furthermore, we aim to elucidate synergy between therapeutic antibodies and antibiotics since our recent studies indicate that MAC can allow antibiotics to pass the otherwise impermeable outer membrane.