Use of a Designer Proline-rich antimicrobial peptide Chaperone protein inhibitor (DPC) for treating antibiotic resistant pneumonia

Project Summary Infectious disease is the third-leading cause of death in the United States, and hospital-acquired infections(HAIs) in particular affect 1.7 million patients annually. The most common type of HAI is pneumonia, often causedby multi-drug resistant (MDR) pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiellapneumoniae, Escherichia coli, and Acinetobacter baumannii. Rates of antibiotic resistance for these bacteria inhospital- and ventilator-acquired pneumonia (HAP and VAP, respectively) have escalated significantly, in somecases exceeding 45%. There is a clear and urgent unmet medical need for new therapeutic strategies totreat HAP and VAP that can improve patient outcomes and combat the rising rates of antibiotic resistanceassociated with HAIs. As a novel approach to address this expanding medical need, Arrevus is pioneering the development ofDesigner Proline-rich antimicrobial peptide Chaperone protein inhibitors (DPCs). The lead compound, ARV-1501, imparts its antimicrobial activity in two distinct ways; i) disrupting the bacterial lipid membrane and ii)specifically inhibiting the bacterial chaperone protein DnaK, a highly conserved prokaryotic heat-shock proteincritical for bacterial survival in stress conditions. In preliminary studies, ARV-1502 has demonstrated broad-spectrum antimicrobial activity against a range ofGram-negative and Gram-positive bacterial pathogens. ARV-1502 has also demonstrated the ability to reversebacterial resistance to legacy antibiotics. In the proposed Phase I program, Arrevus will conduct a series ofstudies to characterize the antibiotic activities of ARV-1502 both in vitro and in vivo in order to assess thepotential of ARV-1502, alone and in combination with an antibiotic, to treat HAP and VAP. In Aim 1, we will use in vitro studies to define the spectrum of activity of ARV-1502 alone (Aim 1A) and incombination with clinically-utilized antibiotics (Aim 1B) against antibiotic-sensitive and antibiotic-resistant strainsof P. aeruginosa. In Aim 2, we will assess ARV-1502 alone and as an adjuvant therapy with the meropenem ina mouse model of pneumonia. In Aim 2A, ARV-1502 will be administered as a monotherapy to characterizeefficacy and dosing for co-treatment in Aim 2B. The collective data from this Phase I effort will define ARV-1502?s ability, alone or with an antibiotic, to treatpneumonia that is typically resistant to legacy antibiotics. These proof-of-concept data are critical to supportfurther development of ARV-1502 in a Phase II program that would be geared toward performing extensive invivo efficacy and safety studies to assess ARV-1502 as a therapeutic option for treating MDR-associated HAPand VAP.