Optimization of Atypical Antimycobacterial Carbapenem Antibiotics

非典型抗分枝杆菌碳青霉烯类抗生素的优化

• 批准号: 10736024
• 负责人: JOHN D BUYNAK
• 金额: $ 75.94万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736024
• 关键词: Acylation; Address; Anabolism; Anti-Bacterial Agents; Antibiotics; Antimycobacterial Agents; Bacteria; Biochemical; Biochemistry; Biological; Biological Availability; Biology; Carbapenems; Cell Wall; Chemicals; Clinical; Crystallography; Cysteine; Data; Development; Drug Kinetics; Enzymatic Biochemistry; Evaluation; Genetic; Genus Mycobacterium; Goals; Homeostasis; Hydrolysis; In Vitro; Infection; Lactamase; Lactams; Lead; Libraries; Mediating; Meropenem; Methodology; Microbiology; Modification; Monobactams; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium tuberculosis; Oral; Outcome; Patient-Focused Outcomes; Penicillin-Binding Proteins; Peptidoglycan; Peptidyltransferase; Pharmaceutical Preparations; Plasma; Positioning Attribute; Predisposition; Prodrugs; Property; Proteins; Qualifying; Regimen; Research; Resistance; Role; Serine; Specificity; Structure-Activity Relationship; Synthesis Chemistry; Therapeutic; Time; Transmembrane Transport; Treatment Protocols; Tuberculosis; VDAC1 gene; analog; antibiotic design; antimicrobial; carbapenemase; crosslink; design; drug candidate; drug discovery; improved; in vitro activity; in vivo; inhibitor; insight; interest; lead optimization; mouse model; multidisciplinary; mycobacterial; non-tuberculosis mycobacteria; non-tuberculous mycobacterial infection; novel; operation; pathogen; pharmacologic; resistant strain; scaffold; stem; structural biology; therapeutic target; tool

Abstract Mycobacterial infections, broadly including Mycobacterium tuberculosis (Mtb), and those caused by nontuberculous mycobacteria (NTM) like the fast-growing Mycobacterium abscessus (Mab), as well as the slow- growing Mycobacterium avium complex (MAC), represent some of the most clinically challenging and deadly infections of the 21st century. Treatments typically involve regimens of multiple antibiotics that are administered for lengthy periods of time, and poor outcomes are common. -Lactam antibiotics have not traditionally been a part of these treatment regimens, due to -lactamase mediated resistance, and because some classes of - lactams lack antimycobacterial activity. Significantly, for peptidoglycan crosslinking, mycobacterial species primarily use an alternate L,D-transpeptidase (Ldt) in place of the canonical D,D-transpeptidase (Ddt) (or penicillin binding protein, PBP), the latter of which is the primary target of typically administered -lactams. Ldts and Ddts are nonhomologous proteins which, in part, explains the apparent ineffectiveness of this drug class against mycobacterial species. This application involves design and synthesis of carbapenem antibiotics with substantial and unusual (atypical) structural alterations, in contrast to existing agents which differ only at the C2 position. Previously, we have demonstrated that these scaffold modifications can improve activity against Gram- negative pathogens, minimize efflux, and improve resistance to -lactamase-mediated hydrolysis. Preliminary studies for this project yielded an atypical carbapenem with superior potency compared to commercially available carbapenems against diverse Mtb and Mab clinical isolates. Unlike meropenem, this new atypical carbapenem maintained its potency against resistant mycobacterial pathogens in the absence of a combination -lactamase inhibitor, displaying up to 20-fold improvements over meropenem in activity against these resistant strains. Its excellent,broad spectrum antimycobacterial potency (MICs < 1 g/ml) was not diminished by carbapenemase producing mycobacterial species nor was activity further improved by combination with -lactamase inhibitors thus indicating -lactamase stability. Activity was also assessed against a diverse panel of nonmycobacterial species indicating the new antibiotic is beginning to demonstrate selectivity for the mycobacteria genus over other Gram-negative and Gram-positive species. We now plan to develop this initial discovery into an orally bioavailable clinically useful antimycobacterial agent and to further improve the antimycobacterial potency and specificity of this unique atypical carbapenem. Stability to carbapenemases will be an asset in an orally bioavailable agent since many carbapenemase inhibitors (e.g. avibactam) are not orally bioavailable. The scientific operations are guided by a highly qualified team including synthesis, microbiology, biochemistry, and structural biology. A thorough and rigorous array of analyses, including numerous in vitro and in vivo PK evaluations, will guide development.

抽象的 分枝杆菌感染，包括结核分枝杆菌（MTB），以及由 非结核分枝杆菌（NTM），例如快速生长的分枝杆菌（mAb），以及慢速 - 种植分枝杆菌鸟体综合体（MAC），代表了一些最具临床挑战性和致命的人 21世纪的感染。治疗通常涉及多种抗生素的方案 在很长一段时间内，很常见的结果很常见。 乳酰胺抗生素传统上并不是 这些治疗方案的一部分是由于-内酰胺酶介导的耐药性，并且由于某些类别的-- lactams缺乏抗菌活性。值得注意的是，对于薄荷糖交联，分枝杆菌种 主要使用替代L，D-转肽酶（LDT）代替规范D，D-转肽酶（DDT）（或 青霉素结合蛋白，pbp），后者是通常给予-内酰胺的主要目标。 LDTS DDT是非同源蛋白，部分解释了该药物类别的明显无效性 对抗分枝杆菌。该应用涉及设计和合成碳青霉烯抗生素 与仅在C2不同的现有药物相比，实质和不寻常的（非典型）结构改变 位置。以前，我们已经证明，这些脚手架的修改可以改善针对革兰事的活动 阴性病原体，最大程度地减少外排，并提高对-内酰胺酶介导的水解的耐药性。初步的 该项目的研究产生了一个非典型的碳青霉烯，与市售 针对潜水MTB和MAB临床分离株的碳青霉烯。与MeropeNem不同，这种新的非典型碳青霉烯 在没有组合-内酰胺酶的情况下，保持其抵抗性分枝杆菌病原体的效力 抑制剂，针对这些抗性菌株的活性表现出比美洛培植物相比的20倍改善。 优秀的宽光谱抗菌效力（MIC <1G/mL）并未通过碳青霉烯酶减少 与-内酰胺酶抑制剂联合使用，产生分枝杆菌物种也不会进一步改善活性 因此表明-内酰胺酶稳定性。还针对非霉菌的潜水员小组评估了活动 表明新抗生素的物种开始证明对分枝杆菌的选择性 其他革兰氏阴性和革兰氏阳性物种。现在，我们计划将此初始发现开发为口头 可生物可利用的临床有用的抗菌剂，并进一步提高抗菌细菌效力和 这种独特的非典型碳青霉烯的特异性。碳碳纤维酶的稳定性将是口服的资产 由于许多碳酸苯甲酶抑制剂（例如，avibactam）不可口服生物利用，因此生物利用剂。这 科学操作由一支高素质的团队指导，包括合成，微生物学，生物化学和 结构生物学。彻底而严格的分析，包括大量体外和体内PK 评估，将指导发展。