Designed Antimicrobial Peptides for Treatment of Infectious Acne Vulgaris

公共摘要。 寻常痤疮是一种慢性炎症性皮肤病，影响80%以上的青少年和年轻人 全世界的成年人痤疮导致大量的皮肤和心理疾病负担，往往造成严重的 影响患者的自尊和社会化。痤疮管理结果在高货币和医生使用 在美国的需求，占每年超过500万人次的医生访问，并导致成本 超过25亿美元。抗生素治疗已成为痤疮管理不可或缺的，但广泛， 抗生素的使用通常是随意的，这导致了耐药痤疮丙酸杆菌的出现。此外，生物膜 痤疮丙酸杆菌形成的，其中包括复杂的微生物菌落包裹在一个有弹性的致密 细胞外基质增加了其对抗微生物剂的抗性。生物膜是。尽管迫切需要 对于具有新作用模式的新抗生素，抗菌剂的开发急剧下降， 近年来由Riptide Bioscience Inc创建的设计的抗微生物肽（dAMP）在化学上是 来源于天然存在的AMP，其在自然界中普遍存在，并提供了针对 入侵的病原体dAMP刺激细菌耐药性的可能性降低，表现出有效的 抗革兰氏阳性痤疮丙酸杆菌病原体的抗微生物活性，并具有已知的抗炎特性。 基于在嗜热链球菌分离株和生物膜培养物中观察到的最初令人鼓舞的抗菌结果， 痤疮并表现出体内抗菌和抗炎活性，我们认为这些新的 肽可以治疗痤疮感染，同时表现出对细菌抗性的较低易感性。在此提出的 为了进行研究，将评估dAMP对痤疮丙酸杆菌分离株和生物膜的体外抗菌活性， 将评估dAMP介导的痤疮丙酸杆菌在不存在和存在皮脂的情况下的杀菌动力学， 将测定dAMP对人角质形成细胞的细胞毒性，并测定铅的抗微生物功效。 将测定肽在炎性痤疮丙酸杆菌鼠模型中改善感染的作用。如果成功， 通过SBIR资助的第二阶段研究，将选择候选产品，以达到FDA要求的 临床前研究，目的是开发一种商业上可行的治疗感染性痤疮的疗法 普通的

Public Abstract. Acne vulgaris is a chronic inflammatory skin disorder affecting more than 80% of all adolescents and young adults worldwide. Acne causes a substantial cutaneous and psychologic disease burden, often creating crippling effects in patients’ self‑esteem and socialization. Acne management results in high monetary and physician use demands in the United States, accounting for more than 5 million doctor visits each year and resulting in costs in excess of $2.5 billion. Antibiotic therapy has been integral to acne management however the widespread, and often permissive, use of antibiotics has led to the emergence of resistant P. acnes bacteria. Moreover, biofilm formation by P. acnes, which comprise sophisticated colonies of microorganisms encased in a resilient dense extracellular matrix increases its resistance against antimicrobial agents. Biofilms are. Despite the critical need for new antibiotics with novel modes of action, the development of antibacterial agents has drastically declined in recent years. Designed antimicrobial peptides (dAMPs), created by Riptide Bioscience Inc, are chemically derived from naturally occurring AMPs which are ubiquitous in nature and provide the first line of defense against invading pathogens. dAMPs have a reduced likelihood of spurring bacterial resistance, exhibit potent antimicrobial activity against the Gram-positive P. acnes pathogen and have known anti-inflammatory properties. Based on the initial encouraging antimicrobial results observed in planktonic isolates and biofilm cultures for P. acnes and demonstrated in vivo antibacterial and anti-inflammatory activity, we propose that these novel peptides may treat acne infections while exhibiting less susceptibility to bacterial resistance. In this proposed investigation, the in vitro antibacterial activity of dAMPs against P. acnes isolates and biofilm will be evaluated, dAMP-mediated P. acnes bactericidal kinetics in the absence and presence of sebum will be assessed, the cytotoxicity of dAMPs on human keratinocytes will be determined and the antimicrobial efficacy of the lead peptides in ameliorating infection in an inflammatory P. acnes murine model will be determined. If successful, a product candidate will be selected to be advanced, via a SBIR grant-funded Phase II study, to FDA-required preclinical studies with the goal of developing a commercially viable therapy for the treatment of infectious acne vulgaris.