DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Novel Antimicrobial Peptides as Topical Anti-Infectives Against Combat-Related Bacterial and Fungal Wound Infections

Posted July 3, 2018

L. Edward Clemens, Ph.D., Riptide Bioscience, Inc.

L. Edward Clemens, Ph.D., Riptide Bioscience, Inc.

Dr. L. Edward Clemens

Ballistic wounds are particularly prone to infection and are hence a threat to the life of Service members.1, 2 The number of available therapies is limited by the multidrug resistance developed by bacteria commonly found in wound infections and the production of biofilms by these bacteria.2 Currently available topical antibiotics have some side effects and limitations including, but not limited to, allergic reactions, poor penetration into the wound, and ineffectiveness against multidrug resistant organisms and fungal infections.1, 3 With support from a Fiscal Year 2014 Military Infectious Diseases Applied Research Award, Dr. Clemens and his colleague Dr. Kathryn Woodburn, sought to develop designed antimicrobial peptides (dAMPs) to address the challenges present in the treatment of ballistic wound infections (BWIs). dAMPs are amphipathic cationic peptides that are designed based on sequences found in naturally occurring antimicrobial peptides. They are believed to have the capacity to disrupt microbes’ membrane function which then rapidly destroys the microbes. Development of a topical drug for the treatment of these BWIs is desperately needed.

Dr. Clemens and his team synthesized around 30 dAMPs and evaluated them for their antimicrobial potency against several bacterial and fungal strains. Multiple assays were performed to determine the potential of dAMPs as anti-infectives. Time-kill assays against Pseudomonas aeruginosa and Staphylococcus aureus were utilized as a preliminary screen for microbial reduction by the peptides. Promising peptides were then evaluated by Minimum Inhibitory Concentration (MIC) assays, which helped determine the lowest peptide concentration that inhibited the growth of the strains. Toxicity assays performed to detect off-target toxicity of these peptides to host cells demonstrated that the dAMPs possess a high therapeutic index4.

Data collected from Dr. Clemens’ work demonstrates that dAMPs are a promising option for the treatment of BWIs. Based on the time-kill assays and consistent with the amphipathic properties of the peptides, dAMPs destroyed bacteria by disrupting their membrane function. Based on the results so far, dAMPs have the potential to both eradicate infection and enhance wound healing while also possessing a reduced likelihood of developing pathogen resistance. Dr. Clemens studied the efficacy of dAMPs to treat BWIs by evaluating the curative potential of three amphipathic peptides (RP504, RP554, and RP557) in a porcine burn wound model infected with P. aeruginosa and S. aureus. These dAMPs have proven to have a broad range of effectiveness against polymicrobial infections residing in biofilm.

The possibility of treating infected wounds with one drug versus multiple drugs for each specific strain present in the wound is encouraging. The ability to rapidly treat infected wounds will diminish the chance for systemic infection, drastically reducing the risk for BWI patients. Further research into dAMPs mechanisms will pave the way for the development of a successful treatment option for BWIs.

References:

1. D'Avignon LC, Saffle JR, Chung KK, and Cancio LC. 2008. Prevention and management of infections associated with burns in the combat casualty. J Trauma 64(3):S277–286.

2. Petersen K, Riddle MS, Danko JR, Blazes DL, Hayden R, Tasker SA, and Dunne JR. 2007. Trauma-related infections in battlefield casualties from Iraq. Ann Surg 245(5):803–811. PMCID: PMC1877069.

3. Horvath EE, Murray CK, Vaughan GM, Chung KK, Hospenthal DR, Wade CE, Holcomb JB, Wolf SE, Mason AD Jr, and Cancio LC. 2007. Fungal wound infection (not colonization) is independently associated with mortality in burn patients. Ann Surg 245(6):978–85. PMCID: PMC1876957.

4. Clemens LE, Jaynes J, Lim E, Kolar SS, Reins RY, Baidouri H, Hanlon S, McDermott AM, Woodburn KW. 2017. Designed host defense peptides for the treatment of bacterial keratitis. Invest Ophthalmol Vis Sci. 58(14):6273-6281.

Link:

Public and Technical Abstracts: Evaluation of Novel Antimicrobial Peptides as Topical Anti-Infectives with Broad-Spectrum Activity against Combat-Related Bacterial and Fungal Wound Infections

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Last updated Tuesday, July 3, 2018