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%以上的青少年和青少年 世界各地的成年人。痤疮会造成严重的皮肤和心理疾病负担，通常会造成严重的后果 对患者自尊和社会化的影响。痤疮管理导致大量金钱和医生使用 在美国的需求，占每年500多万人次的就诊次数，并导致成本 超过25亿美元。抗生素治疗一直是痤疮治疗不可或缺的一部分，尽管这种治疗很普遍，而且 抗生素的使用往往是允许的，导致了耐药痤疮假单胞菌的出现。此外，生物膜 由痤疮假单胞菌形成，它由复杂的微生物菌落组成，包裹在具有弹性的密度中 细胞外基质增加其对抗菌剂的抵抗力。生物膜是。尽管有迫切的需求 对于具有新作用机制的新抗生素，抗菌剂的开发已经急剧下降 在最近几年。由Riptie Bioscience Inc.开发的设计抗菌肽(DAMP)是化学上的 来源于自然界中普遍存在的自然产生的AMP，为预防 入侵的病原体。湿气刺激细菌耐药性的可能性降低，表现出强大的 对革兰氏阳性痤疮假单胞菌具有抗菌活性，并具有已知的抗炎特性。 根据在浮游分离物和生物膜培养中观察到的初步令人鼓舞的抗菌结果，P. 痤疮和在体内表现出的抗菌和抗炎活性，我们建议这些新的 多肽可以治疗痤疮感染，但对细菌耐药性的敏感性较低。在本建议中 研究方面，将评估DAMPS对痤疮假单胞菌和生物被膜的体外抗菌活性， 将评估在没有和存在皮脂的情况下，潮湿介导的痤疮假单胞菌杀菌动力学。 将测定DAMPS对人角质形成细胞的细胞毒性以及铅的抗菌效果 在炎症性痤疮小鼠模型中，将确定多肽在改善感染中的作用。如果成功，则会出现一个 候选产品将通过SBIR赠款资助的第二阶段研究被选为FDA要求的先进产品 旨在开发一种治疗感染性痤疮的商业可行疗法的临床前研究 俗气的人。

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.