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.

摘要 非结核分枝杆菌（NTM）是普遍存在的环境细菌，包括快速和慢速- 生长（RGM和SGM）机会性病原体，并在患者中引起结核病（TB）样肺病 肺部疾病或免疫力低下的病人最常见的RGM和SGM 分别是分枝杆菌和M. Avium complex（MAC）。其他临床重要NTM 包括M. fortutuplant和M. chelonae（RGM）和M. kansasii，M. genavense，M. xenopi和M.猴（SGM）。 通常长达多年的治疗主要包括重新利用和表现不佳的抗生素组合。 对于许多NTM疾病，没有可靠的治疗方案，死亡率很高。 优化利福霉素以克服内在耐药性并改善NTM肺病的治疗。 利福平（RIF）因其对专性病原体M的强效作用而成为结核病治疗的支柱。 结核病（Mtb），有利的药代动力学和良好的渗透到疾病部位。虽然RIF 推荐用于治疗除M.猿猴，其治疗效用没有 除了M之外，kansasii病，与RIF对M. Kansasii和 结核分枝杆菌，但对所有其他非结核分枝杆菌的活性较差。利福霉素对大多数NTM没有达到可接受的疗效 由于与其靶点的多态性或突变无关的内在细菌耐药性引起的疾病， RNA聚合酶的RpoB亚基。相反，我们已经表明，M。细菌内注射 通过利福霉素单加氧酶（ROX）和ADP-核糖基酶（Arr）代谢。通过系统的基因组学 搜索，我们已经确定了这些代谢酶在所有主要的RGM和几个SGM。M. kansassii，in line 对利福平治疗有良好的反应，是Arr阴性。利福霉素糖基化酶和磷酸化酶， 在其他细菌中发现的，是潜在的其他候选人，有助于在一些NTM的内在耐药性。 我们建议描述NTMs的物种特异性利福霉素耐药基因组，并利用这一知识， 克服内在耐药性，合理优化利福霉素种类，提高NTM肺的治疗效果 疾病在初步研究中，我们使用抗ROX的利福必妥（RBT）作为化学起点， ADP-核糖基化，导致对M.类似于RIF的Risessus 针对Mtb（其不窝藏ROX或Arr）。我们将把这种方法扩展到适当的RGM和SGM 根据耐药组发现指导的物种。为治疗M提供临床前开发候选药物。 肺结核和其他Arr阳性NTM肺病，药物化学工作将集中在减少血浆 蛋白质结合并消除由于细胞色素P450诱导引起的药物-药物相互作用，同时维持 效力和有利地渗透到肺部病变中。通过体外和小鼠模型的联合研究， 我们将确定最佳的合作伙伴药物，提供所有口服杀菌利福霉素为基础的组合，可以改善 提高治愈率，缩短疗程。