Novel Biamyxins targeting multidrug resistant Gram-negative bacterial infections - Gram-negative (G-) bacteria are leading causes of healthcare-associated infections (HAIs). According to the U.S. Department of Health and Human Services, over 1 million HAIs occur across the health care system every year in the US, and hospital-acquired HAIs alone are responsible for $28 to $33 billion in potentially preventable health care expenditures annually. Alarmingly, successful treatment of G- infections has become more and more challenging, primarily due to the rapid emergence of multidrug-resistance (MDR) to existing and even newly approved antimicrobial agents in these pathogens. The World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) published their lists of priority pathogens and antibiotic resistance classification in 2017 and 2019, respectively, in which carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Enterobacteriaceae (CRE), and MDR or carbapenem-resistant Pseudomonas aeruginosa (CRPA) are among those of the biggest concern, highlighting the urgent need for discovery and developing novel antibacterial agents for MDR G- infections. To address this need, we have created a new class of antibiotics, the biamyxins (BMX), which are semisynthetic, dimeric polycationic peptides that tightly bind lipopolysaccharide (LPS) in the outer membrane of G- pathogens including CRAB, CRPA, and CRE isolates, thus confer the broad- spectrum G- coverage with potent antimicrobial activity. BMXs are constructed from two identical semisynthetic polymyxin-derived compounds joined by a central linker. Unlike monomeric polymyxins or recent derivatives, we designed novel dimeric peptide-like compounds optimized to bind the LPS of both sensitive and COL-resistant (COL-R) G- pathogens using cooperative binding. This innovative approach engages modern medicinal chemistry guided structural design to maximize potency while minimizing toxicity of BMX molecules. HCC-0010 is our current lead compound and has demonstrated highly promising properties as a therapeutic agent: broad spectrum antibacterial activity, low cytotoxicity, acute safety in rodents, in vivo efficacy in mouse models of septicemia and pneumonia due to multiple G- species including A. baumannii, P. aeruginosa, and K. pneumoniae, and a favorable plasma half-life (~5 hours) and efficient target tissue (lung and epithelial lining fluid) distribution in mice. Further optimization of potency and spectrum and in-depth evaluation of pharmacological and toxicological properties of this lead are proposed in this application. The overarching goal of this proposal is to identify a qualified lead development candidate by Year 4 and pursue an Investigational new drug (IND) candidate through Years 4 and 5, that meets these criteria: 1) acceptable stability, tolerability and physiochemical properties for IV formulation, 2) MIC90s ≤2 µM against clinical isolates (including MDR) of Klebsiella, Acinetobacter, Pseudomonas and E. coli, 3) MIC90s ≤4 µM against MCR-1, MCR-2 and other colistin- resistant G- clinical isolates, 4) low cytotoxicity with a CC50 >50 µM, 5) robust in vivo therapeutic efficacy against MDR G- pathogens, 6) PK/PD parameters to support three times daily or less frequent dosing in humans.
