Development of Bacterial Therapeutics Targeting Bacterial Vaginosis-Associated Bi

针对细菌性阴道病相关双歧杆菌的细菌疗法的开发

• 批准号: 7925857
• 负责人: Laurel A. Lagenaur
• 金额: $ 19.85万
• 依托单位: OSEL, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925857
• 关键词: Accounting; Anogenital venereal warts; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Atopobium vaginae; Bacteria; Bacterial Vaginosis; Biological Products; Biomedical Engineering; Biopsy; California; Chlamydia; Chromosomes; Clinical; Clinical Trials; Coculture Techniques; Collaborations; Communities; Complement; Complex; Development; Discipline of obstetrics; Disease; Ecology; Evolution; Exhibits; Failure; Female of child bearing age; Functional disorder; Gardnerella; Gardnerella vaginalis; Genes; Genital system; Genitourinary system; Gonorrhea; Gynecologic; HIV; HIV Entry Inhibitors; HIV-1; Heterosexuals; Human; Human Herpesvirus 2; Hydrogen Peroxide; In Vitro; Infection; Intervention; Investigation; Lactobacillus; Lead; Length; Life; Light; Microbial Biofilms; Modeling; Organism; Outcome; Pelvic Inflammatory Disease; Phase II Clinical Trials; Plasmids; Positioning Attribute; Predisposing Factor; Pregnancy Outcome; Prevalence; Prevention; Public Health; Recurrence; Regimen; Reproductive Tract Infections; Research; Sexually Transmitted Diseases; Surface; Syndrome; System; Therapeutic; Tissues; Trichomonas; Universities; Urinary tract infection; Vagina; Viral; Virus; Woman; Work; burden of illness; clinical practice; effective therapy; innovation; microbial; microbial community; microbicide; microorganism; novel; novel therapeutic intervention; prevent; public health relevance; therapeutic target; trait; transmission process; vaginal lactobacilli

DESCRIPTION (provided by applicant): This application focuses on the development of a novel bacterial therapeutics targeting bacterial vaginosis (BV)-associated biofilm for the prevention and treatment of recurrent BV using a novel strain of Lactobacillus jensenii with a disrupted pox1 gene in the chromosome that exhibits highly potent activity against a Gardnerella vaginalis strain (ATCC 14018). As an important step to pursue this biofilm intervention strategy, we propose to further evaluate in vitro efficacy of this novel strain to inhibit clinical vaginal isolates of G. vaginalis and Atopobium vaginae in a co-culture model, and ability to prevent the development of Gardnerella- specific biofilm. BV is the most common infection of the reproductive tract among women of childbearing age globally. Control of BV recurrence has emerged as a global issue of concern, in light of its significant prevalence and pathophysiology among women of childbearing age. Epidemiologically, this disruption in vaginal ecology can lead to a serious disease burden of adverse obstetric and gynecologic outcomes, including adverse pregnancy outcomes and pelvic inflammatory disease. BV resembles a sexually transmitted disease (STD) and is positively associated with the acquisition of other STD. Moreover, BV is prominent in regions of the world associated with high HIV transmission rates and enhances viral replication and genital tract shedding of the HIV-1 and HSV-2 viruses, thereby further promoting the spread of STD. BV is a complex polymicrobial syndrome resulting from the depletion of the normal H2O2-producing lactobacilli in the vagina, overgrowth of BV-associated microorganisms, and the establishment of an adherent Gardnerella/Atopobium-specific biofilm. There are no long-term therapies for curing and preventing this frequently recurring BV condition. The recommended antibiotic treatments, the mainstay of current therapy, fail to eradicate biofilm that is an important predisposing factor for BV recurrence. There is an urgent need to develop innovative therapeutic approaches to target BV-associated biofilm. Successful completion of the proposed studies would position us to pursue potential clinical investigations to evaluate biofilm intervention strategies using bioengineered vaginal Lactobacillus. In combination with current antibiotic regimen, this product concept may have a great potential to shift current research or clinical practice paradigms for an effective treatment and prevention of recurrent BV globally. It would decrease the economical burden from repetitive treatments and potential adverse obstetric and gynecologic outcomes, while re-establishing a Lactobacillus-dominant healthy vaginal flora. PUBLIC HEALTH RELEVANCE:

描述(由申请人提供)：本申请专注于开发一种针对细菌性阴道病(BV)相关生物膜的新型细菌疗法，用于预防和治疗复发的BV，使用染色体上pox1基因中断的新菌株简氏乳杆菌，该菌株对阴道加德纳菌菌株(Atcc 14018)表现出高度的活性。作为实施生物被膜干预策略的重要一步，我们建议进一步评估该新菌株在共培养模式下抑制阴道革兰氏菌和阴道阿托波氏菌临床分离株的体外效果，以及防止加德纳氏菌特异性生物被膜发展的能力。BV是全球育龄妇女中最常见的生殖道感染。鉴于BV在育龄妇女中的显著流行率和病理生理学，控制BV复发已成为一个全球关注的问题。从流行病学上讲，这种对阴道生态的破坏可能导致产科和妇科不良结局的严重疾病负担，包括不良妊娠结局和盆腔炎。BV类似于性传播疾病(STD)，与感染其他STD呈正相关。此外，BV在世界上与艾滋病毒传播率高相关的地区非常突出，并加强了艾滋病毒-1和HSV-2病毒的病毒复制和生殖道脱落，从而进一步促进了STD的传播。BV是一种复杂的多菌综合征，其原因是阴道内正常产生过氧化氢的乳酸菌枯竭，BV相关微生物过度生长，以及粘附性Gardnerella/Atopobium特异性生物膜的建立。没有长期的治疗方法来治愈和预防这种频繁复发的BV疾病。推荐的抗生素治疗是目前治疗的主流，但未能根除生物被膜，生物被膜是BV复发的重要易感因素。迫切需要开发针对BV相关生物被膜的创新治疗方法。建议研究的成功完成将使我们能够继续进行潜在的临床研究，以评估使用生物工程阴道乳杆菌的生物膜干预策略。与目前的抗生素方案相结合，这种产品概念可能有很大的潜力改变当前的研究或临床实践范式，在全球范围内有效治疗和预防BV复发。它将减少重复治疗带来的经济负担和潜在的产科和妇科不良后果，同时重建以乳杆菌为主的健康阴道菌群。 公共卫生相关性：