While antibiotics are the main weapons to fight and clear bacterial infection, they can also select for resistant pathogens and disrupt the human gut microflora. Although these ‘collateral damages’ are recognized, we currently lack antimicrobial strategies to break the vicious cycle of antibiotic resistance by counteracting the spread of mobile resistance genes while protecting the integrity of the gut microbiome. This problem is of particular importance in hospital-acquired infections, as resistance genes exist for all known antibiotics in use today and can rapidly spread among clinical pathogens by horizontal gene transfer. Here, we propose a novel approach combining multidrug screens, laboratory evolution, metagenomics and cultivation-based phenotyping of individual-specific microbiomes to discover novel differentially selective treatment strategies for high-risk clinical infections. First, we are using a high-throughput cell viability screening approach to identify conserved and robust “selection-inverting” antibiotic combinations that can be used to clear resistant pathogens orders of magnitude more efficiently than its susceptible counterpart.