Lysterases as first-in-class prophylactic topical antimicrobials to prevent postsurgical shoulder infections

莱斯特酶作为一流的预防性局部抗菌剂，可预防术后肩部感染

• 批准号: 10080363
• 负责人: James K. Wang
• 金额: $ 25.86万
• 依托单位: DERMALYTICA, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-14 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080363
• 关键词: Acne; Acute; Address; Adopted; Age; Antibiotic Resistance; Area; Bacteria; Bacteriophages; Biological Assay; Budgets; Cells; Characteristics; Clinical; Collaborations; Collection; Cosmetics; Data; Dermatologic; Development; Diagnosis; Digit structure; Family; Family member; Future; Gender; Genetic Variation; Genomics; Implant; Incidence; Infection; Infection prevention; Joints; Knowledge; LytA enzyme; Measures; Medical; Medical Care Costs; Methods; Microbial Biofilms; Molecular; Mycobacteriophages; Operative Surgical Procedures; Orthopedic Surgery procedures; Orthopedics; Outcome; Patients; Penetration; Phase; Phylogenetic Analysis; Prevention; Production; Propionibacterium; Propionibacterium acnes; Protocols documentation; Replacement Arthroplasty; Risk; Sebum; Shoulder; Site; Skin; Small Business Innovation Research Grant; Surgeon; Surgical incisions; Techniques; Technology; Testing; Time; TimeLine; Topical Antibiotic; Universities; Washington; aging population; antimicrobial; genome analysis; genome sequencing; implantable device; medical schools; microbiota; novel; pathogen; pathogenic bacteria; phase 2 study; preclinical development; prevent; prophylactic; research clinical testing; screening; success; whole genome

Orthopedic surgeries to reconstruct and replace joints are increasingly in demand due to an aging population and improvements in materials and techniques. However, postsurgical infections are also of increasing concerns and are difficult to treat, often requiring revision surgeries that add to patient suffering and medical costs. This problem is particularly acute in shoulder arthroplasty, where robust aseptic protocols are not effective in preventing infections due to Cutibacterium (formerly Propionibacterium) acnes, an opportunistic pathogen enriched in sebum-rich sebaceous follicles that are found in abundance in the shoulder area. Dermalytica is developing first-in-class antimicrobials that target pathogenic bacteria without impacting healthy microbiota. A novel and diverse class of mycobacteriophage-encoded lytic enzymes can selectively and rapidly lyse C. acnes, the bacterial culprit in acne. Dermalytica is developing these lytic enzymes as selective topical antimicrobials that can penetrate sebaceous follicles as acne treatments, and the target product profile is similar to that for prevention of shoulder arthroplasty postsurgical infections. We propose to obtain proof-of-concept data on screening a panel of diverse lytic enzymes for their ability to kill a broad range of C. acnes clinical isolates obtained from shoulder surgeries that have been fully sequenced and molecularly characterized. Success in the proposed studies will enable a comprehensive screen for suitable candidates to undergo preclinical development as a first-in- class prophylactic antimicrobial to prevent shoulder arthroplasty infections and address this acute unmet medical need.

由于老龄化，重建和替换关节的骨科手术需求越来越大 人口和材料和技术的改进。然而，术后感染是 也越来越多的关注和难以治疗，往往需要翻修手术，增加了 患者痛苦和医疗费用。这个问题在肩关节成形术中尤其严重， 在稳健的无菌方案不能有效预防由皮肤杆菌引起的感染的情况下， （以前称为丙酸杆菌）痤疮，一种富含皮脂的机会致病菌， 在肩部区域发现大量的卵泡。Dermalytica正在开发一流的 针对致病菌而不影响健康微生物群的抗菌剂。一种新颖且 多种分枝杆菌噬菌体编码的裂解酶可以选择性地快速裂解C. 痤疮，痤疮的细菌罪魁祸首。Dermalytica正在开发这些溶解酶， 局部抗菌剂，可以渗透皮脂腺毛囊作为痤疮治疗，和目标 产品特征与用于预防肩关节置换术后感染的产品特征相似。我们 建议获得关于筛选一组不同溶解酶的概念验证数据， 能够杀死大范围的C。从肩部手术中获得的痤疮临床分离株， 进行了完整的测序和分子鉴定。建议的研究如获成功， 全面筛选合适的候选药物，以进行临床前开发， 类预防性抗菌剂，以防止肩关节置换术感染，并解决这一急性 未满足的医疗需求