SQ641, new drug candidate to treat NTM infections

SQ641，治疗NTM感染的新候选药物

• 批准号: 7744465
• 负责人: VENKATA M REDDY
• 金额: $ 29.47万
• 依托单位: SEQUELLA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744465
• 关键词: Anabolism; Animal Model; Animals; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Bacteria; Blood; CD4 Positive T Lymphocytes; Capromycin; Cell Count; Cell Line; Cell Membrane Permeability; Cell Wall; Cells; Cessation of life; Clinical; Clinical Trials; Complex; Cosmetic surgery; Disease; Environment; Enzymes; Evaluation; Genus Mycobacterium; Growth; HIV; Hospitals; Human; Immune; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Infection prevention; Interferon Type II; Investigational Drugs; Knock-out; Life; Lung; Lung diseases; Mammalian Cell; Microbial Biofilms; Modeling; Mouse Strains; Mus; Mycobacterium Infections; Mycobacterium avium Complex; Mycobacterium tuberculosis; Nucleosides; Organ; Organism; Peptidoglycan; Pharmaceutical Preparations; Phase; Predisposition; Preparation; Procedures; Property; Research Proposals; Resistance; Small Business Innovation Research Grant; Soft Tissue Infections; Soil; Source; Specificity; TNF gene; Toxic effect; Trauma; Tumor Necrosis Factor-alpha; Water; analog; antimicrobial drug; bactericide; chemotherapeutic agent; drug candidate; human TNF protein; human disease; in vitro activity; in vivo; killings; macrophage; mouse model; mycobacterial; preclinical study; public health relevance; research clinical testing; tuberculosis drugs

DESCRIPTION (provided by applicant): Mycobacterium avium complex (MAC) and M. abscessus (MAB) are the two most common nontuberculous mycobacteria (NTM) that cause human disease, and the incidence of NTM infections has been increasing worldwide. Both the organisms are generally resistant to standard antimybacterial drugs and other antibiotics. Hence, there is an critical need for new antimicrobial agents to treat these infections. Capuramycins (CM) are a new class of nucleoside antibiotics that inhibit bacterial cell wall construction by blocking biosynthesis of peptidoglycan (PG). Because PG is unique to bacteria, antibiotics that inhibit its biosynthesis selectively target bacteria with less toxicity to the host. Even though PG is present in all bacteria, CM and analogues have a narrow spectrum of activity, with highest activity against Mycobacteria sp. We investigated several compounds in this class and identified SQ641 as the most active compound with excellent in vitro activity against M. tuberculosis and several NTM. Under this SBIR phase I research proposal, we intend to extend our in vitro studies with SQ641 to include more NTM strains and to investigate SQ641 activity against several different MAC and MAB strains in macrophages and appropriate animal models. These studies will determine whether SQ641 should advance to investigational new drug (IND)-directed preclinical studies in preparation for human clinical trials. PUBLIC HEALTH RELEVANCE: Mycobacterium avium complex (MAC) and M. abscessus (MAB) are the two most common nontuberculous mycobacteria (NTM) that cause human disease. Both are ubiquitous environmental organisms able to thrive in harsh conditions in soil or water. Both NTM can cause cavitary or nodular lung disease in individuals with preexisting lung conditions, or disseminated disease in HIV infected individuals with low blood CD4+ T-cell count (MAC) or infection of the soft tissues following trauma-inducing hospital procedures or cosmetic surgery (MAB). Infections with NTM are invariably acquired from environmental sources and are not contagious. Both MAC and MAB are generally resistant to standard anti-TB drugs and have variable susceptibility to second-line anti-TB drugs. Hence, the existing antimicrobial agents are inadequate to treat MAC and MAB infections and there is an immense need for new antimicrobial agents. Capuramycins (CM) are a new class of nucleoside antibiotics that inhibit bacterial cell wall by blocking biosynthesis of peptidoglycan (PG), a cell wall constituent unique to bacteria. Even though PG is present in all bacteria, CM are most effective against mycobacteria. We investigated several compounds in this antibiotic class and identified SQ641 as the most active, with excellent in vitro activity against a limited number of MAC and MAB strains. Under this SBIR phase I research proposal we intend to extend our in vitro studies with SQ641 to include more NTM strains and to investigate its activity against MAC and MAB in macrophages and appropriate animal models. These studies are essential to advance the drug for clinical evaluation in human NTM infections.

性状（由申请方提供）：鸟分枝杆菌复合体（MAC）和M.结核分枝杆菌（MAB）是引起人类疾病的两种最常见的非结核分枝杆菌（NTM），并且NTM感染的发病率在全球范围内呈上升趋势。这两种微生物通常对标准抗分枝杆菌药物和其他抗生素具有耐药性。因此，迫切需要新的抗微生物剂来治疗这些感染。卡普霉素（Capuramycins，CM）是一类新型的核苷类抗生素，通过阻断肽聚糖（PG）的生物合成来抑制细菌细胞壁的构建。由于PG是细菌所独有的，因此抑制其生物合成的抗生素选择性地靶向对宿主毒性较小的细菌。尽管PG存在于所有细菌中，但CM及其类似物的活性谱很窄，对分枝杆菌属的活性最高。我们研究了这类化合物，并确定SQ641是最具活性的化合物，对分枝杆菌具有优异的体外活性。结核病和几种NTM。根据SBIR I期研究提案，我们打算扩展SQ641的体外研究，以包括更多的NTM菌株，并研究SQ641对巨噬细胞和适当动物模型中几种不同MAC和MAB菌株的活性。这些研究将决定SQ641是否应该进入研究性新药（IND）指导的临床前研究，为人体临床试验做准备。公共卫生相关性：鸟分枝杆菌复合群（MAC）和M。结核分枝杆菌（MAB）是引起人类疾病的两种最常见的非结核分枝杆菌（NTM）。两者都是无处不在的环境生物，能够在土壤或水中的恶劣条件下茁壮成长。这两种NTM均可在既存肺部疾病的个体中引起空洞性或结节性肺病，或在具有低血CD4+ T细胞计数（MAC）的HIV感染个体中引起播散性疾病，或在创伤诱导的医院程序或整容手术（MAB）后引起软组织感染。NTM感染总是从环境来源获得，并且不具有传染性。MAC和MAB通常对标准抗结核药物具有耐药性，对二线抗结核药物具有可变的敏感性。因此，现有的抗微生物剂不足以治疗MAC和MAB感染，并且对新的抗微生物剂存在巨大的需求。Capuramycins（CM）是一类新型核苷类抗生素，其通过阻断肽聚糖（PG）的生物合成来抑制细菌细胞壁，肽聚糖是细菌特有的细胞壁成分。尽管PG存在于所有细菌中，但CM对分枝杆菌最有效。我们研究了这类抗生素中的几种化合物，并确定SQ641是最具活性的，对有限数量的MAC和MAB菌株具有优异的体外活性。根据SBIR I期研究提案，我们打算扩展SQ641的体外研究，以纳入更多的NTM菌株，并研究其在巨噬细胞和适当动物模型中对MAC和MAB的活性。这些研究对于推进药物在人类NTM感染中的临床评价至关重要。