The goal of the project is to use a cellular infection model to study the activation of effector mechanisms in the natural immunity, such as antimicrobial peptides (AMP), autophagy and free oxygen radicals, which can contribute to the killing of resistant bacteria. We are already working on compounds that increase AMP production and activate autophagy, such as vitamin D and phenylbutyrate (PBA). In clinical studies, we have shown that vitamin D can reduce the burden of infection in immunosuppressed patients and that the combination of vitamin D and PBA can improve outcomes in tuberculosis. Now we have identified several new AMP inducers (APDs) that are more potent than both vitamin D and PBA. We have shown that an APD activates human macrophages and enables these cells to kill Klebsiella bacteria. The effect relies on a combination of free oxygen radicals, AMP and autophagy, making it extremely difficult for bacteria to develop resistance to this massive and coordinated immune attack. Interestingly, this APD also works against multidrug-resistant Klebsiella bacteria and together with cefotaxime a potent and synergistic effect is seen. Cefotaxime alone has no effect at all against these multi-resistant bacteria, but together with this APD, which activates the cell's own immune system, the resistant bacteria also die. "Now we want to go further and investigate the mechanisms in detail, include more bacteria, start animal studies and plan for clinical trials.