DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Development of Novel Kinocidin-Based Anti-Infective Therapeutics

Principal Investigator: YEAMAN, MICHAEL R
Institution Receiving Award: LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT HARBOR-UCLA MEDICAL CENTER
Program: DMRDP
Proposal Number: DM110399
Award Number: W81XWH-12-2-0101
Funding Mechanism: Military Infectious Diseases Applied Research Award
Partnering Awards:
Award Amount: $1,979,057.81


PUBLIC ABSTRACT

U.S. military personnel face increased risk of infection by pathogenic microbes. Moreover, conditions of warfare and combat injury pose the additional risk of infection due to organisms that are resistant to conventional antibiotics or for which vaccines are not available. In a variety of settings, U.S. military personnel face risks of superficial or penetrating wound injuries, burns, suboptimal hygiene, sleep dysregulations, heightened physical and/or emotional stress, and suboptimal nutrition -- all of which further reduce immune defenses and increase vulnerability to infection.

The principal goal of this project is to rapidly accelerate a novel anti-infective and immune enhancement technology designed to protect U.S. military and defense personnel from resistant and emerging pathogens. Application of a novel and antibiotic-enhancing anti-infective agents that act also to amplify the immune system would be a breakthrough advance in protecting military and defense personnel. The kinocidin peptide technology is designed to achieve this very goal. The peptide technology is designed from proteins that are expressly designed by nature to function systemically in the human bloodstream or in a targeted manner directed at wound sites. This strategy overcomes the historical limitations of classical antimicrobial peptides, which have been fraught with key issues of stability in blood and/or toxicity. The novel peptides directly inhibit or kill multidrug-resistant pathogens, amplify white blood cell function, work together with conventional antibiotics, and may speed wound healing. Together, these features make the technology in the current study of especially high relevance to the U.S. military.

The proposed research follows a strategic and highly logical plan to accelerate preclinical development and lay an ideal groundwork for immediate follow-on clinical testing. The study molecules will first be prioritized for efficacy against Gram-negative bacterial pathogens of utmost importance to U.S. military wounds and injuries. To do so, the studies will define mechanisms of action of the peptides versus these organisms alone and in combination with existing antibiotics. Next, we will translate the most effective peptide and peptide plus antibiotic combinations to animal models of infection caused by these life-threatening bacteria. Lastly, we will accelerate preclinical production of the lead peptides through studies designed to optimize commercially scalable manufacturing.

The proposed peptide technology represents breakthrough biological agents that have striking and amplified efficacy against dangerous pathogens in human blood, highly favorable safety profiles, and the ability to increase while blood cell defenses and that function in a favorable way with conventional antibiotics. Therefore, accelerating the preclinical development of this exciting new anti-infective technology to address antibiotic-resistant pathogens directly and to enhance immune defenses and wound healing is an urgent and high priority to protect U.S. military personnel.