Optimization of rifamycins to overcome intrinsic resistance of nontuberculous mycobacteria to improve treatment of NTM lung disease

优化利福霉素以克服非结核分枝杆菌的内在耐药性，改善 NTM 肺病的治疗

• 批准号: 10713137
• 负责人: Courtney C Aldrich
• 金额: $ 85.76万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-06 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713137
• 关键词: ADP ribosylation; Acceleration; Acute; Aging; Antibiotics; Automobile Driving; Bacteria; Bacterial Infections; Binding Proteins; Biological Assay; CYP3A4 gene; Chemicals; Chronic; Clinical; Combined Antibiotics; Complement; Complex; Cytochrome P450; DNA-Directed RNA Polymerase; Data; Development; Diagnostic; Disease; Dose; Drug Interactions; Drug Kinetics; Ensure; Environment; Enzymes; Exhibits; Future; Genetic Polymorphism; Genomics; Goals; Immunity; Immunocompromised Host; In Vitro; Individual; Industry Standard; Infection; Knock-out; Knowledge; Lead; Learning; Lung; Lung diseases; Measures; Metabolic; Metabolism; Mixed Function Oxygenases; Mutation; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium chelonae; Mycobacterium fortuitum; Mycobacterium kansasii; Mycobacterium tuberculosis; Mycobacterium xenopi; Naphthoquinones; Natural Resistance; Nodule; Oral; Outcome; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phosphorylases; Plasma Proteins; Play; Predisposition; Property; Publishing; Pulmonary Pathology; Pulmonary Tuberculosis; Recommendation; Refractory; Regimen; Resistance; Rifabutin; Rifampin; Rifamycins; Role; Site; Sputum; Testing; Therapeutic; Tuberculosis; analog; bacterial resistance; bactericide; clinically relevant; comorbidity; cystic fibrosis patients; efficacy study; global health; improved; in vivo; lung injury; lung lesion; mortality; mouse model; mutant; mycobacterial; non-tuberculosis mycobacteria; novel; opportunistic pathogen; oxidation; pathogen; pre-clinical; preclinical development; prevent; programs; response; treatment duration; tuberculosis treatment

ABSTRACT Non-tuberculosis mycobacteria (NTM) are ubiquitous environmental bacteria comprising rapid- and slow- growing (RGM and SGM) opportunistic pathogens and causing tuberculosis (TB)-like lung disease in patients with pre-existing lung conditions or compromised immunity. The most frequently encountered RGM and SGM are Mycobacterium abscessus and the M. avium complex (MAC), respectively. Other clinically important NTM include M. fortuitum and M. chelonae (RGM), and M. kansasii, M. genavense, M. xenopi, and M. simiae (SGM). The often multiyear-long treatment consists of mostly repurposed and underperforming antibiotic combinations. For many NTM diseases, there is no reliable curative regimen and mortality is high Our overarching goal is to optimize rifamycins to overcome intrinsic resistance and improve treatment of NTM lung disease. Rifampicin (RIF) is the pillar of TB therapy owing to its exquisite potency against the obligate pathogen M. tuberculosis (Mtb), favorable pharmacokinetics and excellent penetration to the sites of disease. Although RIF is recommended for the treatment of all SGM pulmonary diseases but M. simiae, its therapeutic utility has not been established except for M. kansasii disease, in line with RIF being similarly potent against M. kansasii and Mtb but poorly active against all other NTMs. Rifamycins do not achieve acceptable efficacy against most NTM diseases due to intrinsic bacterial resistance not associated with polymorphisms or mutations in their target, the RpoB subunit of the RNA polymerase. Rather, we have shown that M. abscessus undergoes intrabacterial metabolism by rifamycin monooxygenase(s) (ROX) and ADP-ribosylase (Arr). Through systematic genomics searches, we have identified these metabolic enzymes in all major RGM and several SGM. M. kansassii, in line with its favorable response to rifampicin treatment, is Arr-negative. Rifamycin glycosylases and phosphorylases, discovered in other bacteria, are potential additional candidates contributing to intrinsic resistance in some NTM. We propose to characterize the species-specific rifamycin resistome of NTMs and exploit this knowledge to overcome intrinsic resistance and rationally optimize the rifamycin class to improve the treatment of NTM lung disease. Using ROX-resistant rifabutin (RBT) as chemical starting point in preliminary studies, we have blocked ADP-ribosylation, resulting in a dramatic potency improvement against M. abscessus, similar to that of RIF against Mtb (which does not harbor ROX or Arr). We will expand this approach to appropriate RGM and SGM species as guided by resistome findings. To deliver a preclinical development candidate for the treatment of M. abscessus and other Arr-positive NTM lung diseases, medicinal chemistry efforts will focus on reducing plasma protein binding and removing drug-drug interactions due to cytochrome P450 induction, while maintaining potency and favorable penetration into lung lesions. Through combination studies in vitro and in mouse models, we will identify best partner drugs to deliver all-oral bactericidal rifamycin-based combinations that can improve cure rates and shorten treatment duration.

抽象的 无链核分枝杆菌（NTM）是无处不在的环境细菌，包括快速和慢速 - 患者的生长（RGM和SGM）机会病原体并引起结核病（TB）类似肺部疾病 具有先前存在的肺部状况或免疫力损害。最常遇到的RGM和SGM 分别是脓肿分枝杆菌和大鸟分枝杆菌（MAC）。其他临床上重要的NTM 包括M. fortuitum和M. chelonae（RGM），以及M. Kansasii，M。Genavense，M。Xenopi和M. Simiae（SGM）。 通常，多年的治疗方法由大部分重新利用和表现不佳的抗生素组合组成。 对于许多NTM疾病，没有可靠的治愈方案，死亡率很高，我们的总体目标是 优化利福非霉素以克服内在抗性并改善对NTM肺部疾病的治疗。 利福平（RIF）是结核病治疗的支柱，这是由于其针对强制性病原体M的效力。 结核病（MTB），有利的药代动力学和出色的疾病部位穿透。虽然rif 建议治疗所有SGM肺部疾病，但Simiae M. Simiae，其治疗效用尚未 除Kansasii疾病外，还建立了RIF对Kansasii和M. kansasii和 MTB，但对所有其他NTM的活跃。利福霉素不能针对大多数NTM实现可接受的功效 由于固有的细菌抗性引起的疾病，与其靶标的多态性或突变有关 RNA聚合酶的RPOB亚基。相反，我们已经表明，腹部腹部经历了细菌性的 利福米霉素单加氧酶（S）（ROX）和ADP-核糖基酶（ARR）代谢。通过系统的基因组学 搜索，我们已经在所有主要的RGM和几个SGM中确定了这些代谢酶。 M. Kansassii，排队 凭借其对利福平治疗的有利反应，是ard-negative。利福米霉素糖基酶和磷酸酶，磷酸盐酶 在其他细菌中发现的是潜在的其他候选者，这些候选者在某些NTM中有助于内在抗性。 我们建议表征NTMS的物种特异性利由霉素的抗性，并将这些知识利用为 克服固有抗性并合理优化利福米霉素类，以改善NTM肺的治疗 疾病。在初步研究中，使用耐Rox的利法布丁（RBT）作为化学起点，我们已经阻止了 ADP-核糖基化，导致针对超麻子菌的巨大效力，类似于RIF 反对MTB（不藏有ROX或ARR）。我们将将这种方法扩展到适当的RGM和SGM 由抵抗组引导的物种。提供用于治疗的临床前开发候选者。 腹肌和其他ARR阳性NTM肺疾病，药物化学工作将重点放在减少血浆 由于细胞色素P450诱导而导致的蛋白质结合并去除药物 - 药物相互作用，同时保持 效力和良好的渗透到肺部病变中。通过体外和小鼠模型的组合研究， 我们将确定最佳伴侣药物以提供基于全口杀菌杀菌利由霉素的组合，可以改善 治愈率和缩短治疗持续时间。