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 非结核分枝杆菌 (NTM) 是普遍存在的环境细菌，包括快速和慢速细菌 生长（RGM 和 SGM）机会性病原体并导致患者出现结核 (TB) 样肺部疾病 已有肺部疾病或免疫力受损。最常遇到的RGM和SGM 分别是脓肿分枝杆菌和鸟分枝杆菌复合体（MAC）。其他临床上重要的 NTM 包括偶然分枝杆菌和龟分枝杆菌 (RGM)，以及堪萨斯分枝杆菌、格纳文分枝杆菌、蟾蜍分枝杆菌和猿分枝杆菌 (SGM)。 通常长达数年的治疗主要由重新调整用途且效果不佳的抗生素组合组成。 对于许多 NTM 疾病，没有可靠的治疗方案，死亡率很高。我们的首要目标是 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 的卓越功效而成为结核病治疗的支柱。 结核病 (Mtb)，良好的药代动力学和对疾病部位的良好渗透性。虽然RIF 被推荐用于治疗所有 SGM 肺部疾病，但 M. simiae 除外，其治疗效用尚未见报道。 除堪萨斯分枝杆菌疾病外，RIF 也对堪萨斯分枝杆菌疾病具有同样的效力，并且 Mtb 但在对抗所有其他 NTM 时表现不佳。利福霉素对大多数 NTM 没有达到可接受的疗效 由于内在细菌耐药性而导致的疾病与目标的多态性或突变无关， RNA 聚合酶的 RpoB 亚基。相反，我们已经证明脓肿分枝杆菌经历细菌内 利福霉素单加氧酶 (ROX) 和 ADP-核糖基酶 (Arr) 的代谢。通过系统基因组学 通过搜索，我们已经在所有主要 RGM 和几个 SGM 中识别出这些代谢酶。 M. kansassii，排队 由于对利福平治疗有良好反应，因此呈 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 NTM 是导致某些 NTM 内在耐药性的潜在其他候选者。 我们建议表征 NTM 的物种特异性利福霉素抗性组，并利用这些知识来 克服内在耐药合理优化利福霉素类别改善NTM肺治疗 疾病。在初步研究中，使用 ROX 抗性利福布丁 (RBT) 作为化学起点，我们已经阻断了 ADP-核糖基化，导致对抗脓肿分枝杆菌的效力显着提高，与 RIF 类似 对抗 Mtb（不包含 ROX 或 Arr）。我们将把这种方法扩展到适当的 RGM 和 SGM 以抗性组发现为指导的物种。提供治疗结核分枝杆菌的临床前开发候选药物。 脓肿和其他 Arr 阳性 NTM 肺部疾病，药物化学工作将集中于减少血浆 蛋白质结合并消除由于细胞色素 P450 诱导而导致的药物间相互作用，同时保持 效力和对肺部病变的有利渗透。通过体外和小鼠模型的组合研究， 我们将确定最佳的合作药物来提供基于利福霉素的全口服杀菌组合，可以改善 治愈率和缩短治疗时间。