Small molecule antibiotic drug development for Combating Antibiotic Resistant Bacteria (CARB)

Skin and soft tissue infections caused by the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are of serious concern for hospitalized Wounded Warriors. These infections are often MDR can lead to amputations, amputation revision, sepsis, and death. Current antibiotics are becoming less efficacious as resistance is being built into the military population. A new therapeutic with extensive coverage and acceptance is required.

The goal of this program is to develop an effective antibacterial small molecule or compound class that overcomes drug resistance mechanisms in a narrow (genus) or broad (gram-negative) spectrum of multidrug-resistant (MDR) clinical isolates. The prototype compound (pre-clinical candidate) must be efficacious against clinically-relevant gram negative bacteria in animal infection models, have clinically acceptable pharmacokinetics and dynamics for oral or parenteral administration, and a low-to-acceptable toxicity profile.

The research project award recipient was selected from the Offerors who responded to MTEC’s Request for Project Proposals (19-04-WRAIR-CARB).

Dual Activities of Novel Lipoxygenase Inhibitors to Combat Gram-negative Pathogens and Sepsis

Project Team: SRI International
Award Amount: $1.95M
Project Duration: 36 months
Project Objective: This project aims to advance a novel class of dual lipoxygenase (LOX) inhibitors with direct bactericidal activity and anti-inflammatory properties to combat Gram-negative bacteria, limit tissue damage and, potentially, provide superior therapeutic benefit as compared with traditional treatments for bacterial infection. We will conduct lead-optimization, complete the evaluation of LOX inhibitors through preclinical development, and identify promising therapeutic compounds for future studies to support investigational new drug (IND) applications and their clinical development to treat Gram-negative bacterial infection.  Furthermore, developing a new class of antibiotics with novel targets for which there is no pre-existing resistance will help fight multidrug-resistant bacterial infection.