Selective antimicrobial peptides from milk for bacterial vaginosis

牛奶中的选择性抗菌肽治疗细菌性阴道病

基本信息

批准号：
10484181
负责人：
Bruce German
金额：
$ 28.7万
依托单位：
MATRUBIALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-10 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10484181
关键词：
Acute Address Age Anti-Bacterial Agents Anti-Infective Agents Antibiotics Antimicrobial Resistance Bacteria Bacterial Vaginosis Biological Assay Categories Cell Survival Cells Chromatography Clindamycin Clinical Coculture Techniques Communicable Diseases Communities Complex Development Economic Burden Escherichia coli Faculty Family Female Foundations Gardnerella vaginalis Gram-Negative Bacteria Grant HIV HIV/STD Health Homeostasis Human Human Milk Immune response In Vitro Infant Development Infection Inflammation Inflammatory Klebsiella Lactation Lactobacillus Lead Link Listeria monocytogenes Metronidazole Milk Modeling Multi-Drug Resistance Outcome Pelvic Inflammatory Disease Peptides Phase Porphyromonas gingivalis Pre-Clinical Model Predisposition Premature Birth Premature Labor Preparation Probiotics Pseudomonas aeruginosa Public Health Recurrence Relapse Research Research Personnel Resistance Safety Salmonella enteritidis Sexually Transmitted Diseases Small Business Innovation Research Grant Spontaneous abortion Staphylococcus aureus Structure-Activity Relationship Testing Therapeutic Tissues Topical application Toxic effect Translating Vagina Variant Well in self Woman Women&apos s Health Work antimicrobial antimicrobial peptide beta-Casein cervicovaginal clinically relevant commensal bacteria drug modification dysbiosis efficacy testing follow-up global health host microbiome in vivo in vivo evaluation innovation lead candidate microbiota novel novel therapeutic intervention novel therapeutics pathogen pathogenic bacteria polymicrobial biofilm pre-clinical pressure priority pathogen programs recurrent infection reproductive reproductive tract resistance mutation response side effect synergism synthetic peptide transmission process vaginal lactobacilli vaginal microbiome vaginal microbiota

项目摘要

Project Abstract Several currently administered antibiotics raise two main concerns: resistance and non-selectivity. The rapid rate of emerging multi-drug resistance poses a global health threat and dramatically increases economic burden. With traditional antibiotics being largely non-selective, there are serious side effects due to the natural host microbiome being modified, and thus a loss in homeostasis. The strong need for innovative, potent, naturally occurring and specifically selective therapeutics have prompted us to explore for such bioactive molecules in milk. The result of 200 million years of evolutionary pressure, mammalian lactation guides the development of the infant and provides protection from a wide-variety of infections. Upon fractionating thousands of naturally occurring peptides from human milk, and discovering their antibacterial activity, we have focused on the function and mechanism of action of novel antimicrobial peptides from human milk. One such peptide, HBCA2, an internal 12-mer sequence of human b-casein rapidly eliminates the viability of gram-positive and gram-negative bacteria, including but not limited to Category 1 priority pathogens. We have made the key observation that Gardnerella vaginalis, a major bacterial vaginosis (BV)-associated pathogen, is susceptible to HBCA2, whereas the viability of key lactobacilli linked to a healthy vaginal microbiome remains unaltered. BV remains an unmet need, with few treatment options and high rates of recurrence resulting in several public health concerns for women of reproductive age. It is associated with outcomes including to not limited to pre-term labor, STI and HIV transmissions, and other reproductive challenges. We propose HBCA2, a milk-borne, antimicrobial peptide, with its unique selectivity feature of inertness towards commensal bacteria, as a lead candidate molecule in topical applications for the treatment of BV—a therapy that could in turn reduce the burden of BV outcomes. In this phase I SBIR grant, we will evaluate a larger range of G. vaginalis strains other bacterial vaginosis associated bacteria as well as a larger number of vaginal and probiotic lactobacilli for their response to HBCA2 and variants of HBCA2 synthesized to enhance efficacy. Additionally, we will determine the HBCA2 mechanism of action, examine its efficacy and/or synergy to traditional antimicrobials, characterize resistance mutations (if any), analyze the direct effect of HBCA2 on mammalian host cells and determine the impact of function on infection and inflammation in pre- clinical infection models of the female reproductive tract. This work will aid the preparation for Phase II, where we will test HBCA2 in in vivo efficacy and early safety PK studies, and determine cervicovaginal tissue impact and immune response. Ultimately, this proposal will allow us to further characterize HBCA2 alone or in combination with additional such peptides as potent antibacterial therapeutic, derived from milk, which can be employed for treatment of recurrent BV via topical applications.

项目摘要目前使用的几种抗生素引起了两个主要问题：耐药性和非选择性。快速出现的多重耐药性对全球健康构成威胁并急剧增加由于传统抗生素基本上是非选择性的，因此存在严重的副作用。由于天然宿主微生物组被改变，从而失去了体内平衡的强烈需求。创新的、有效的、自然发生的和特异性选择性的疗法促使我们探索牛奶中的此类生物活性分子是两亿年进化压力的结果，哺乳动物的哺乳指导婴儿的发育并提供保护免受多种因素的影响从母乳中分离出数千种天然存在的肽，以及在发现其抗菌活性后，我们重点研究了其功能和作用机制。来自母乳的新型抗菌肽，HBCA2，一种内部 12 聚体。人 B-酪蛋白序列可快速消除革兰氏阳性菌和革兰氏阴性菌的活力细菌，包括但不限于1类优先病原体，我们做了重点观察。阴道加德纳菌是一种主要的细菌性阴道病 (BV) 相关病原体，易受 HBCA2，而与健康阴道微生物组相关的关键乳酸杆菌的活力仍然存在 BV 仍然是一个未得到满足的需求，治疗选择很少且复发率很高。导致育龄妇女的一些公共卫生问题。结果包括但不限于早产、性传播感染和艾滋病毒传播以及其他生殖疾病我们提出了 HBCA2，一种乳源性抗菌肽，具有独特的选择性特征。对共生细菌的惰性，作为局部应用的主要候选分子 BV 治疗——一种可以反过来减轻 BV 结果负担的疗法。在第一阶段 SBIR 资助中，我们将评估更大范围的阴道加德纳菌菌株和其他细菌阴道病相关细菌以及大量阴道和益生菌乳酸菌对 HBCA2 的反应以及合成的 HBCA2 变体以增强功效。确定 HBCA2 的作用机制，检查其功效和/或与传统药物的协同作用抗菌药物，描述耐药突变（如果有），分析 HBCA2 对抗菌药物的直接影响哺乳动物宿主细胞并确定其功能对感染和炎症的影响女性生殖道的临床感染模型这项工作将有助于第二阶段的准备。我们将测试 HBCA2 的体内功效和早期安全性 PK 研究，并确定宫颈阴道最终，该提案将使我们能够进一步表征。 HBCA2单独或与其他此类肽组合作为有效的抗菌治疗剂，源自牛奶，可通过局部应用治疗复发性 BV。