SUMMARY
Diabetic foot ulcers (DFUs) are non-healing chronic wounds that develop upon skin
injury in patients with poorly controlled diabetes mellitus (DM). One quarter of DM
patients develop a DFU in their lifetime and, despite standard care, one in three DFUs
fails to heal. DFU patients are highly susceptible to rapidly spreading infection that can
lead to soft tissue damage and osteomyelitis, lower limb amputation (~100,000 annually
in the USA), sepsis, and death. Most DFU infections are polymicrobial, and traditional
therapies that target only one microorganism usually have a poor outcome in treating
polymicrobial infections. Furthermore, polymicrobial DFU communities often form
biofilms that are highly resistant to antibiotics. Currently, the standard DFU treatment is
surgical debridement (i.e., removal of healing-impaired tissue harboring polymicrobial
biofilms) and offloading to relieve the pressure from the affected foot. Despite treatment,
DFUs often do not heal for weeks, months or even years. DFUs are treated with
antibiotics when there are clinical signs of infection, but antibiotic therapy very often
fails. Thus, DFU treatment is challenging and there is a need for new therapies.
The goal of this application is to determine in vitro, ex vivo, and in vivo efficacy of the
novel antimicrobial cyclic lipopeptide CLP4 on polymicrobial wound biofilms composed
of the clinically relevant bacterial DFU isolates, and to determine the impact of CLP4 on
the healing of infected wounds. In vivo local and systemic acute toxicity of CLP4 will
also be determined. The results of this project will provide preclinical data for the
development of an innovative DFU treatment.