Antibiotic resistance presents an ever increasing challenge to the public health. Conventional screening paradigms in antibiotic discovery are based on MIC/MBC testing in conventional bacteriologic media, and similar tests on patient isolates are used to guide physician management. A single-minded focus on direct antimicrobial activities overlooks the fact that significant infections are really a disease of the host-pathogen interaction. Indeed, before the patient has even seen a doctor, their infection is already being treated by multiple antimicrobials - namely the cellular and molecular components of the innate immune system. We see value in exploring potential novel therapeutic approaches for drug-resistant bacteria that aim to tip the host-pathogen interaction back in favor of the host, e.g. by re-sensitize the pathogen to innate immune killing or directly boost the antibacterial killing capacity of host cells. In this new discovery and treatment framework, drugs used in medicine for other indications, or antibiotics otherwise deemed ineffective, can be “rediscovered” or “repurposed" for treatment of multi-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) or carbapenemase-resistant strains of Gram-negative pathogens including Acinetobacter baumannii and Pseudomonas aeruginosa. Finally, we are developing and testing novel biomimetic nanoparticle drugs, in which the drug entity is a host cell membranes derived from RBCs, platelets and macrophages. The “nanosponge” therapeutics allow the capture and sequestration of microbial toxins and endotoxins and excessive host cytokines during severe pneumonia and sepsis, and lie poised for entry into human clinical trials.