Targeting the Urgent Need for New Antibiotics against Gram-negative ‘Superbugs’

针对针对革兰氏阴性“超级细菌”的新型抗生素的迫切需求

• 批准号: 10219081
• 负责人: Jian Li
• 金额: $ 84.05万
• 依托单位: MONASH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219081
• 关键词: Acids; Acinetobacter baumannii; Advanced Development; Agreement; Americas; Amino Acids; Animal Model; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Attention; Australia; Back; Bacteria; Biology; Centers for Disease Control and Prevention (U.S.); Chemicals; Clinic; Clinical; Colistin; Combating Antibiotic Resistant Bacteria; Communicable Diseases; Country; Dangerousness; Data; Development; Disease Outbreaks; Drug Kinetics; Evaluation; Financial Support; Future; Gram-Negative Bacteria; Healthcare; Hospitals; Human; Incidence; Infection; International; Klebsiella pneumoniae; Lead; Licensing; Life; Lung infections; Mediation; Medical; Medicine; Microbiology; Modeling; Modification; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Non-Rodent Model; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physicians; Plasmids; Polymyxin B; Polymyxin Resistance; Polymyxins; Positioning Attribute; Property; Pseudomonas aeruginosa; Reporting; Research; Research Design; Research Proposals; Resistance development; Rodent; Safety; Series; Societies; Structure; Structure-Activity Relationship; Superbug; System; Therapeutic; Time; Toxic effect; Translations; Universities; acute toxicity; bacterial resistance; base; candidate selection; cost; design; drug candidate; drug discovery; emerging pathogen; experience; global health; improved; innovation; lead candidate; multidrug-resistant Pseudomonas aeruginosa; nephrotoxicity; novel; novel therapeutics; pathogen; pharmacokinetics and pharmacodynamics; preclinical development; programs; virtual

Background: The world is facing an enormous and growing threat from the emergence of bacterial ‘superbugs’. If bacteria continue developing resistance to multiple antibiotics at the present rate and at the same time the antibiotic pipeline continues to dry up, there could be catastrophic costs to healthcare and society globally. Numerous hospitals worldwide have experienced outbreaks of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. All of these pathogens are on the IDSA ‘hit list’ of the six top-priority dangerous bacteria that require urgent attention to discover new antibiotics. Polymyxins (i.e. colistin and polymyxin B) are used as the ‘last-line’ of therapy for infections caused by these very problematic Gram-negative pathogens. Unfortunately, the clinical utility of polymyxins is hindered by their nephrotoxicity and poor efficacy against lung infections due to pharmacokinetic limitations. Unfortunately, plasmid-borne resistance to polymyxins has been reported recently. In essence, polymyxin resistance implies a total lack of antibiotics for treatment of deadly infections caused by these Gram-negative bacteria. Clearly, the development of new antibiotics is urgently needed. All three of these Gram-negative bacteria are the focus of this project. Research Design: Building upon our systematic polymyxin pharmacology research over the last 17 years, this project will employ our novel structure-activity relationship (SAR) and structure-toxicity relationship (STR) models to rationally develop novel, safer polymyxin-like lipopeptides that target Gram-negative ‘superbugs’ including polymyxin-resistant isolates. The Specific Aims are: (1) To employ our well established lipopeptide medicinal chemistry platform to design, synthesize and microbiologically evaluate approximately 300 novel lipopeptides against MDR K. pneumoniae, P. aeruginosa and A. baumannii; (2) To conduct lead candidate selection based upon acute toxicity, efficacy and nephrotoxicity in animal models, and MICs against an extended panel of clinical isolates. Upon completion of Aim 2, a lead candidate lipopeptide and a back-up will be selected for further development (Specific Aim 4). (3) To elucidate the mechanisms of antibacterial activity and nephrotoxicity of our polymyxin- like lipopeptides using systems pharmacology and chemical biology. These mechanistic studies will improve our SAR/STR models and benefit the IND application; and (4) To develop the lead candidate (and a back-up) for IND-enabling studies based upon evaluations of the stability, toxicity, PK and PK/PD using rodent and non- rodent models. The results from Specific Aim 4 will also provide essential efficacy and toxicity data to support future IND-enabling studies. Even though it is beyond the scope of this RFA, we are very enthusiastic that the identified lead candidate will be taken into IND-enabling studies with financial support from Rempex-MedCo. Significance: Our innovative proposal will develop much-needed safer and more efficacious polymyxins to counteract the current global health crisis caused by Gram-negative ‘superbugs’.

背景：世界正面临着来自新冠病毒的出现的巨大且日益严重的威胁。 细菌“超级细菌”。如果细菌继续对多种抗生素产生耐药性 目前的速度，同时抗生素管道继续枯竭，有 可能会给全球医疗保健和社会带来灾难性的成本。多家医院 全球范围内爆发了由多重耐药性（MDR）引起的感染 铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌。所有这些 病原体属于 IDSA 六种最优先危险细菌的“重点打击名单”，需要 迫切关注发现新的抗生素。使用多粘菌素（即粘菌素和多粘菌素 B） 作为治疗这些非常有问题的革兰氏阴性菌引起的感染的“最后一线” 病原体。不幸的是，多粘菌素的临床应用因其肾毒性而受到阻碍 由于药代动力学限制，对肺部感染的疗效较差。很遗憾， 最近报道了质粒传播的多粘菌素耐药性。从本质上讲，多粘菌素 耐药性意味着完全缺乏抗生素来治疗引起的致命感染 由这些革兰氏阴性细菌。显然，迫切需要开发新的抗生素。 所有这三种革兰氏阴性细菌都是该项目的重点。研究设计：建筑 根据我们过去 17 年的系统性多粘菌素药理学研究， 项目将采用我们新颖的结构-活性关系（SAR）和结构-毒性 关系（STR）模型来合理开发新型、更安全的多粘菌素样脂肽 针对革兰氏阴性“超级细菌”，包括多粘菌素耐药菌株。具体目标是： （1）利用我们成熟的脂肽药物化学平台进行设计、合成 并对大约 300 种新型脂肽进行微生物学评估，以对抗 MDR K。 肺炎杆菌、铜绿假单胞菌和鲍曼不动杆菌； （二）进行牵头候选人遴选 基于动物模型中的急性毒性、功效和肾毒性以及针对某种药物的 MIC 临床分离株的扩展组。完成目标 2 后，主要候选脂肽和 将选择备份进行进一步开发（具体目标 4）。 (3) 阐明机制 使用系统研究我们的多粘菌素样脂肽的抗菌活性和肾毒性 药理学和化学生物学。这些机制研究将改进我们的 SAR/STR 模型 有利于IND申请； (4) 开发支持 IND 的主要候选药物（和后备候选药物） 基于使用啮齿动物和非动物对稳定性、毒性、PK 和 PK/PD 进行评估的研究 啮齿动物模型。具体目标 4 的结果还将提供基本的功效和毒性 数据支持未来的 IND 支持研究。尽管这超出了本 RFA 的范围，但我们 非常热衷于确定的主要候选人将被纳入 IND 启用研究 Rempex-MedCo 的财务支持。意义：我们的创新提案将得到发展 急需更安全、更有效的多粘菌素来应对当前的全球健康危机 由革兰氏阴性“超级细菌”引起。

项目成果

A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening Acinetobacter baumannii.

• DOI: 10.1039/d1sc03460j
• 发表时间: 2021-09-22
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Jiang X;Patil NA;Azad MAK;Wickremasinghe H;Yu H;Zhao J;Zhang X;Li M;Gong B;Wan L;Ma W;Thompson PE;Yang K;Yuan B;Schreiber F;Wang L;Velkov T;Roberts KD;Li J
• 通讯作者: Li J

Critical Role of Position 10 Residue in the Polymyxin Antimicrobial Activity.

• DOI: 10.1021/acs.jmedchem.2c01915
• 发表时间: 2023-02
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: N. Patil;Wendong Ma;Xukai Jiang;Xiao-shu He;Heidi H. Yu;Hasini Wickremasinghe;Jiping Wang;P. Thompson-P

Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment.

通过对粘菌素治疗前后个体患者的多重耐药肺炎克雷伯菌分离株进行基因组分析，揭示了粘菌素耐药的多方面机制。

• DOI: 10.1016/j.jinf.2019.07.009
• 发表时间: 2019
• 期刊: The Journal of infection
• 作者: Zhu,Yan;Galani,Irene;Karaiskos,Ilias;Lu,Jing;Aye,SuMon;Huang,Jiayuan;Yu,HeidiH;Velkov,Tony;Giamarellou,Helen;Li,Jian
• 通讯作者: Li,Jian

Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

慢性肾病患者使用粘菌素：我们是否给患者用药剂量不足？

• DOI: 10.3390/molecules24030530
• 发表时间: 2019
• 期刊: Molecules (Basel, Switzerland)
• 作者: Sorli,Luisa;Luque,Sonia;Li,Jian;Rodríguez,Eva;Campillo,Nuria;Fernandez,Xenia;Soldado,Jade;Domingo,Ignacio;Montero,Milagro;Grau,Santiago;Horcajada,JuanP
• 通讯作者: Horcajada,JuanP

Complete genome sequence and genome-scale metabolic modelling of Acinetobacter baumannii type strain ATCC 19606.

鲍曼不动杆菌型菌株 ATCC 19606 的完整基因组序列和基因组规模代谢模型。

• DOI: 10.1016/j.ijmm.2020.151412
• 发表时间: 2020
• 期刊: International journal of medical microbiology : IJMM
• 作者: Zhu,Yan;Lu,Jing;Zhao,Jinxin;Zhang,Xinru;Yu,HeidiH;Velkov,Tony;Li,Jian
• 通讯作者: Li,Jian