Novel Cyclic Lipopeptides for Treating Complicated Wound Infections
Abstract
Prevention of tissue injury and enhancement of wound healing are urgent military needs. However, despite the advances in the medical care provided to injured military personnel and civilians, wound infections remain one of the major challenges facing the U.S. military caregivers. The treatment of these infections has become exceedingly difficult, not only because of bacterial resistance to antibiotics but also because bacteria form biofilms that are resistant to host defense and antimicrobial treatment. Bacterial biofilms are particularly problematic in the case of persistent and recurrent infections. A number of antibiotics have been evaluated for the prevention and disruption of biofilms, but few have proven to be effective. Although limited therapeutic options are presently available for the treatment of complicated wound infections, in order to provide effective treatment options for the future, innovative antibiotics are urgently needed, preferably with novel modes of action and/or belonging to novel classes of drugs. Cyclic lipopeptides derived from fusaricidin/LI-F natural products represent a chemically distinct class of antibacterial agents with the potential to meet the challenge of bacterial resistance to antibiotics. These peptides exhibit potent in vitro activity against multidrug-resistant bacteria, including bacterial biofilms. Their promising in vivo antibacterial activity was demonstrated by prevention of methicillin-resistant Staphilococcus aureus (MRSA) growth in a porcine wound model with no signs of erytherema and edema. Therefore, cyclic lipopeptides are particularly attractive candidates for the development of a new class of antibacterial agents. To further develop cyclic lipopeptides as preclinical antibiotic leads for prevention and treatment of complicated combat-related or trauma-induced wound infections, we will utilize a multidisciplinary approach that combine synthetic peptide chemistry with polymer chemistry to prepare an optimal antibacterial/antibiofilm formulation for topical application and assess this formulation efficacy in a porcine wound model. Once completed, the proposed research will pave the way for more extensive preclinical studies and advancement of novel cyclic lipopeptide antimicrobials to clinical trials. Our proposed research directly addresses the Fiscal Year 2014 Military Infectious Diseases Applied Research Award Focus Area: Development and preclinical testing of novel chemotypes as potential therapeutics or prophylactics for wound infection and biofilm formation, maintenance, or propagation. The overall long-term goal of the proposed research is to develop novel cyclic lipopeptide antibiotics as an alternative to the existing options for topical treatment of infected acute wounds in the combat as well as chronic wounds in Department of Veterans Affairs system, including those caused by multidrug-resistant organisms and biofilms. Finding alternative treatment options for the combatant may significantly reduce infection rates, in particular, infections caused by multidrug-resistant pathogens, and provide a better quality of life to injured Soldiers. Not only would this information be relevant for military personnel, but it might provide better therapeutic options for civilian caregivers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510657
Entities
People
- Predrag Cudic
Organizations
- Torrey Pines Institute for Molecular Studies
- United States Army