Research Project
9618286
Urinary tract infections (UTIs) are one of the most common hospital-acquired infections and are often caused by multi-drug resistant (MDR) bacterial pathogens. MDR bacterial pathogens are associated with significant morbidity and mortality, creating enormous healthcare and economic burdens due to variations in disease natural histories as well as the lack of effective therapeutic options. Treatment option limitations are particularly relevant for MDR Gram-negative pathogens, such as Escherichia coli and Klebsiella pneumoniae, which have shown a great propensity to challenge the clinical care of patients. Arrevus is developing a novel approach to addressing complicated UTIs caused by MDR Enterobacteriaceae through the use of Designer Proline-rich Antimicrobial peptide Chaperone protein inhibitors (DPCs), derived from insects and selectively modified, acting as inhibitors to one of the critical bacterial proteins responsible for bacterial protein folding, DnaK. As an adjuvant therapy to current antibiotics, DPCs have the potential to provide a much-improved treatment option for MDR Gram- negative bacterial infections. Preliminary studies have displayed the potential of ARV-1502, the lead DPC, as an antibiotic potentiating agent against MDR Gram-negative bacterial pathogens. Our efforts have shown that: 1) DPCs enhance antibiotic activity; 2) DPCs reduce bacterial burden in a UTI model; 3) ARV-1502 has a favorable preliminary safety profile; 4) ARV-1502 provides an enhancement of the effects of antimicrobial agents through a novel MOA; and 5) ARV- 1502 has demonstrable activity in murine MDR Gram-negative bacteremia models. Collectively, these data support the continued development of AVR-1502 through an STTR Phase I program targeting proof-of-concept data for the use of ARV-1502 in the treatment of complicated UTIs. The proposed Phase I program will involve in vitro assessments, including minimum inhibitory concentration assays and checkerboard assays, to characterize the activity of ARV-1502 with and without legacy antibiotics against uropathogens and the evaluation of the potential of resistance development to ARV-1502 (Aim 1). Successful completion of Aim 1 will identify an optimal ARV-1502/antibiotic pairing. This optimal combination will then be assessed in a mouse UTI model against several uropathogens (Aim 2). ARV-1502 activity will be assessed alone and in combination with the antibiotic identified in Aim 1 in order to determine bacterial burden reduction. This Phase I program will provide the necessary proof-of-concept data to support further development of ARV-1502 in a Phase II program that will center on extensive in vivo efficacy studies and preliminary safety studies.
