Hospital-Acquired Infections (HAI) have become a health care crisis and are a leading cause of death. Further the hospital setting harbors a reservoir of lethal multidrug resistant (MDR) organisms, two million patients suffer from HAI annually, resulting in 100,000 deaths and up to $4.5 billion in additional health care expense. Thus, there is a global health emergency due to the growing prevalence of infections caused by MDR HAI pathogens. To combat these pathogens, we introduce GmPcides, a novel family of ring-fused 2-pyridone compounds that are bactericidal against a broad spectrum of Gram-positive species, including all seven Gram-positive species identified by the CDC as among the most significant antibiotic-resistant threats. These bacteria include Clostridioides difficile, vancomycin-resistant Enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Streptococcus pneumoniae (S. pneumoniae), erythromycin-resistant Group A Streptococcus (S. pyogenes) and clindamycin-resistant Group B Streptococcus (S. agalactiae). Significantly, GmPcides are active against non-dividing bacteria and at sub-lethal doses, can disarm resistance, to re- sensitize MDR microbes to antibiotic treatment, both in vitro and in vivo in a murine model of HAI infection to standard-of-care antibiotics targeting multiple orthogonal processes. GmPcides have no effect on Gram- negative viability or significant toxicity to host tissues. Our group developed GmPcides by combining the talents of synthetic chemist Dr. Fredrik Almqvist with microbiologists Drs. Michael Caparon and Scott Hultgren who propose to take advantage of their understanding of HAI pathogenesis and their unprecedented ability to manipulate the substituent diversity of the 2-pyridone scaffold to address issues essential for the translation of GmPcides, including: i) optimization of activity, stability and solubility through structure-activity relationship (SAR) and structure-property relationship (SPR) studies; ii) Identification of the GmPcide target(s) using a systems-level chemical-genetic approach and the comprehensive genetic resources available for the model Gram-positive organism Bacillus subtilis; iii) optimization of activity against HAI bacteria growing in biofilm communities; and iv) assessment of the in vivo efficacy of improved GmPcides in murine models of HAI urinary tract and soft tissue infection. These experiments described here will lead to the identification of critical druggable target(s) highly conserved among Gram-positive HAI pathogens and will lead to the development of new antibiotic-sparing and antibiotic-disarming therapies to combat the challenge of MDR HAI Gram-positive pathogens. .