Inhaled nisin as an emergency intervention against antibiotic sensitive or resist

吸入乳链菌肽作为对抗抗生素敏感或耐药的紧急干预措施

• 批准号: 7480537
• 负责人: Kenneth Alibek
• 金额: $ 29.98万
• 依托单位: AFG BIOSOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480537
• 关键词: Animals; Anthrax Vaccines; Anthrax disease; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacillus anthracis; Bacillus anthracis spore; Bacterial Infections; Bacterial Spores; Binding; Biological Warfare; Bioterrorism; Biothrax; Breathing; Caring; Categories; Cells; Cessation of life; Ciprofloxacin; Clinical Research; Development; Disease; Disease Progression; Dose; Doxycycline; Drug Formulations; Emergency Situation; Engineering; Event; Exposure to; Food Preservatives; Future; Germination; Goals; Hospitals; Immunity; Individual; Infection; Infectious Agent; Inhalators; Intervention; Learning; Lung; Military Personnel; Mus; Nisin; Other Therapy; Peptides; Pharmaceutical Preparations; Prevention; Principal Investigator; Process; Production; Prophylactic treatment; Public Health; Range; Reproduction spores; Respiratory System; Risk; Safety; Skin; Standards of Weights and Measures; Surface; Technology; Testing; Time; Toxin; Treatment Protocols; United States Food and Drug Administration; Vaccination; Vaccines; aerosolized; anthrax toxin; base; day; design; disorder prevention; dosage; emergency service responder; falls; mouse model; prevent; programs; response; success

DESCRIPTION (provided by applicant): The deliberate release of Bacillus anthracis spores remains an imminent threat both in terms of bioterrorism and biowarfare. Individuals who inhale these spores are at extreme risk of infection and death from anthrax. Current prophylaxis and therapy in the event of B. anthracis spore inhalation fall into two categories. Vaccination to protect against future exposure, and antibiotic therapy to treat systemic bacterial infections. The commercially available anthrax vaccine requires 6 doses over 18 months for full efficacy and while there have been some non-clinical studies of post exposure vaccination, this has not yet been proven to be helpful for prevention of disease. Antibiotic therapy, usually with ciprofloxacin, is effective only after the inhaled spores germinate and grow as vegetative cells, at which time two anthrax toxins are expressed. It is possible to engineer antibiotic resistant strains of B. anthracis that would render antibiotics ineffective. B. anthracis spores themselves are inert and do not express toxin until they germinate and grow vegetatively, thus it would be of great utility to have a product which could neutralize inhaled spores prior to germination thus keeping them inert until they can be cleared from the body. The lantibiotic peptide nisin has the unique capacity to bind to and neutralize bacterial spores, including B. anthracis spores and spores isolated from antibiotic-resistant B. anthracis. By binding to the spore surface, nisin arrests the germination process. Nisin has received a "Generally Recognized As Safe" designation from the FDA, is currently widely used as a food preservative, and is used in various topical veterinary products. The goal of this submission is to develop an inhaled nisin formulation that could be used in addition to conventional antibiotics and other anthrax therapies in the event of exposure to inhaled anthrax spores. It is the only know intervention that can be used on an emergency basis to neutralize inhaled spores. This product would be deployed with first responders and military personnel in the form of a disposable inhaler to be used immediately after suspected spore inhalation to neutralize the inhaled spores in the lungs prior to germination and toxin production. This proposal will test the capacity of nisin to protect animals against pulmonary challenge with anthrax spores and examine the safety of nisin delivery to the lungs. PUBLIC HEALTH RELEVANCE: Anthrax remains a serious bioterrorism/biowarfare threat. Spores of Bacillus anthracis are relatively easy to produce and disseminate, and the "weaponization" process makes these spores even more effective bioterrorism agents. One of the lessons learned from the events of 2001 is that infections resulting from deliberate exposure to anthrax spores, especially weaponized spores, can be very difficult to treat. In the event of an attack with anthrax spores, victims exposed to the spores can receive several treatments to try to prevent disease progression. The current standard of care is long term dosing of antibiotics like ciprofloxin or doxycycline which can be administered for as long as 60 days. Vaccines, like Biothrax (Emergent Biosolutions) can also be administered immediately after exposure with the hope of generating some protective immunity, but this vaccine requires six doses over eighteen months to be fully protective. Currently, there are no products specifically designed to neutralize spores in the respiratory tract. Anthrax spores are the infectious agent of B. anthracis, but by themselves are inert and not pathogenic. The spores must germinate and grow vegetatively to express toxins, and being able to neutralize inhaled spores in the lungs and prevent their germination could help prevent disease. Optimally, such a neutralizer, which prevent the germination of all spores, but neutralization of even a percentage of the spores would give the other therapies a better chance for success. There is an immediate need for a product specifically designed to neutralize anthrax spores in the respiratory tract. This product should be extremely safe and be able to be formulated in such a way that it can be used in the field in situations and in hospitals where anthrax spore exposure is suspected as an additional layer of protection beyond the use of antibiotics, post exposure vaccinations and other therapies in development. This submission proposes to develop an inhaled product that can neutralize inhaled anthrax spores before they germinate and grow to cause systemic and fatal disease. This product is intended as an addition to other anthrax therapies. Currently there is no such product is available.

描述（由申请人提供）：蓄意释放炭疽芽孢杆菌孢子在生物恐怖主义和生物战方面仍然是迫在眉睫的威胁。吸入这些孢子的人极有可能感染炭疽病并死亡。目前对于吸入炭疽芽孢杆菌孢子的预防和治疗分为两类。疫苗接种可防止未来暴露，抗生素治疗可治疗全身细菌感染。市售炭疽疫苗需要在 18 个月内接种 6 剂才能完全发挥功效，虽然已经进行了一些暴露后疫苗接种的非临床研究，但尚未证明这有助于预防疾病。抗生素治疗（通常使用环丙沙星）只有在吸入的孢子发芽并生长为营养细胞后才有效，此时会表达两种炭疽毒素。有可能设计出对抗生素具有抗性的炭疽芽孢杆菌菌株，从而使抗生素失效。炭疽芽孢杆菌孢子本身是惰性的，在发芽和营养生长之前不会表达毒素，因此，拥有一种能够在发芽前中和吸入孢子的产品，从而使它们保持惰性，直到它们从体内清除为止，将非常有用。羊毛硫抗生素肽乳链菌肽具有独特的能力，可以结合并中和细菌孢子，包括炭疽芽孢杆菌孢子和从耐抗生素炭疽芽孢杆菌中分离的孢子。通过与孢子表面结合，乳链菌肽阻止发芽过程。乳链菌肽已获得 FDA 的“公认安全”称号，目前广泛用作食品防腐剂，并用于各种外用兽药产品中。本次提交的目的是开发一种吸入乳链菌肽制剂，在接触吸入炭疽孢子的情况下，除了传统抗生素和其他炭疽疗法外，还可以使用该制剂。这是唯一已知的可在紧急情况下用于中和吸入孢子的干预措施。该产品将以一次性吸入器的形式部署在急救人员和军事人员中，在吸入可疑孢子后立即使用，以在发芽和产生毒素之前中和肺部吸入的孢子。该提案将测试乳链菌肽保护动物免受炭疽芽孢肺部攻击的能力，并检查乳链菌肽输送到肺部的安全性。公共卫生相关性：炭疽仍然是严重的生物恐怖主义/生物战威胁。炭疽杆菌的孢子相对容易产生和传播，“武器化”过程使这些孢子成为更有效的生物恐怖主义制剂。从 2001 年事件中汲取的教训之一是，因故意接触炭疽孢子（尤其是武器化孢子）而导致的感染可能非常难以治疗。如果发生炭疽孢子袭击，接触孢子的受害者可以接受多种治疗，以防止疾病进展。目前的护理标准是长期服用环丙沙星或多西环素等抗生素，最长可服用 60 天。 Biothrax（Emergent Biosolutions）等疫苗也可以在接触后立即注射，希望产生一些保护性免疫力，但这种疫苗需要在十八个月内注射六剂才能发挥充分保护作用。目前，还没有专门设计用于中和呼吸道孢子的产品。炭疽孢子是炭疽芽孢杆菌的传染原，但其本身是惰性的且不致病。孢子必须发芽并无性生长才能释放毒素，能够中和肺部吸入的孢子并阻止其发芽有助于预防疾病。最理想的是，这样的中和剂可以防止所有孢子的萌发，但即使中和一定比例的孢子也会给其他疗法带来更好的成功机会。迫切需要一种专门设计用于中和呼吸道中炭疽孢子的产品。该产品应该非常安全，并且能够以这样的方式配制，即可以在怀疑炭疽孢子暴露的现场和医院中使用，作为除使用抗生素、暴露后疫苗接种之外的额外保护层以及其他正在开发的疗法。该提案建议开发一种吸入产品，可以在吸入的炭疽孢子发芽和生长导致全身性致命疾病之前将其中和。该产品旨在作为其他炭疽疗法的补充。目前尚无此类产品可用。