Multidrug-resistant (MDR)-bacteria are on the rise globally and there is an urgent need to develop novel antibiotics that will transform the way we treat bacterial infections and combat MDR-bacteria. In contrast to currently available antibiotic targets (e.g. cell wall, DNA, RNA and protein synthesis), we will target the energy-generating machinery of bacterial pathogens, the power-plant of the cell, a step change for antibiotic development. We have termed these new antibiotics ""metabiotics"" because they target a metabolic process. We have identified and validated NADH hydrogenase (NDH-2) as an essential component of this machinery and solved the first bacterial NDH-2 structure, establishing a framework for the structure-based design of small-molecule inhibitors – metabiotics – which will be tested in vitro and in vivo against MDR-pathogens. The outcome of this work will be the development of ground-breaking metabiotics that combat all pre-existing resistance mechanisms of MDR-bacteria and reduce patient treatment time and costs.