Targeting polymicrobial infections of diabetic foot ulcers with a novel antimicrobial peptide therapy

总结 糖尿病足溃疡（DFU）是在皮肤上形成的不愈合的慢性伤口 糖尿病（DM）控制不佳的患者中的损伤。DM的四分之一 患者在其一生中会发生DFU，尽管接受了标准治疗， 无法愈合DFU患者对快速传播的感染非常敏感， 导致软组织损伤和骨髓炎、下肢截肢（每年约100，000例 在美国）、败血症和死亡。大多数DFU感染是多种微生物， 仅靶向一种微生物的疗法通常在治疗 多种微生物感染此外，多微生物DFU群落通常形成 对抗生素具有高度抗性的生物膜。目前，标准DFU治疗是 外科清创术（即，去除含有多种微生物的愈合受损组织 生物膜）和卸载以减轻来自受影响足部的压力。尽管接受了治疗， DFU通常数周、数月甚至数年都不会愈合。DFU的治疗方法为 当有感染的临床症状时，使用抗生素，但抗生素治疗通常 失败了因此，DFU治疗具有挑战性，需要新的治疗方法。 本申请的目的是确定本发明的组合物的体外、离体和体内功效。 新型抗微生物环脂肽CLP 4对多微生物伤口生物膜的影响 的临床相关细菌DFU分离株，并确定CLP 4对 感染伤口的愈合CLP 4的体内局部和全身急性毒性将 也要坚决。该项目的结果将为临床前数据提供 一个创新的DFU治疗的发展。

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.