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

摘要 -- 糖尿病足溃疡(DFU)是一种在皮肤上形成的不可愈合的慢性伤口 糖尿病(DM)控制不良患者的伤害。四分之一的DM 患者在一生中会发展成DFU，尽管有标准的护理，每三个DFU中就有一个 无法痊愈。DFU患者非常容易受到迅速传播的感染，这种感染可以 导致软组织损伤和骨髓炎、下肢截肢(每年约100,000 在美国)、败血症和死亡。大多数DFU感染是多菌的，而且是传统的 只针对一种微生物的治疗方法通常效果不佳。 多菌感染。此外，多菌DFU群落通常形成 对抗生素具有高度抗药性的生物膜。目前，DFU的标准治疗是 外科清创(即切除含有多种微生物的受损愈合组织 生物膜)和卸载，以减轻受影响脚的压力。尽管接受了治疗， DFU通常几周、几个月甚至几年都不会痊愈。DFU的治疗是 当临床出现感染迹象时使用抗生素，但抗生素治疗非常频繁 失败了。因此，DFU的治疗具有挑战性，需要新的治疗方法。 这项应用的目标是确定体外、体外和体内的疗效 新型抗菌环状脂肽CLP4在创面多菌生物膜上的合成 临床相关细菌DFU的分离情况，并确定CLP4对 感染伤口的愈合。CLP4的体内局部和全身急性毒性 也要有决心。该项目的结果将为临床前研究提供数据 开发一种创新的DFU治疗方法。

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.