Abstract In the United States, skin and soft tissue infections (SSTIs) are one of the most common indications for antibiotic treatment, representing 10% of hospital admissions and 6 million doctor visits a year. SSTIs range from self- limiting furuncles and cellulitis to life-threatening sepsis and tissue necrosis. Recent studies suggest more than 50% of all SSTIs were caused by staphylococcal or streptococcal species, in particular, methicillin-resistant staphylococcus aureus (MRSA). We have engineered a novel class of cell-penetrating antimicrobial therapeutics, called CAHPs, which demonstrate broad-spectrum activity against clinically relevant Gram+ and Gram- pathogens, while exhibiting minimal toxicity in human cells. These compounds have been shown to penetrate infected target cells, breakdown established bacterial biofilms of Category B and C pathogens, and to act as anti-inflammatory agents. Identifying a CAPH lead candidate as a novel therapeutic agent for the treatment of, initially, cutaneous infections addresses a highly unmet medical need. Ultimately, its use can be expanded into a broad spectrum antimicrobial therapeutics. The initial product will be an IV formulation that can be administered in community and nosocomial settings. An IV formulation is preferable for treating systemic cSSTIs, especially if hospital-acquired, and could later also be supplemented with a topical product for use in both communal and hospital settings. The Phase I portion of this proposal will involve characterization of the current prelead candidates for their antimicrobial potency and in vitro toxicity as well as for their pharmacokinetic characteristics. The most promising candidate will be tested in in vivo efficacy models of systemic and topical infections and assessed for its exploratory safety profile. The end result of this work will be a novel, first-in-class antibacterial drug candidate for treatment if SSTIs ready for preclinical development activities leading to the opening of an IND. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.