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：世界正面临着巨大而日益严重的威胁 细菌“超级细菌”。如果细菌继续在该地区发展对多种抗生素的抗性 目前的速率，同时抗生素管道继续干燥，那里 在全球范围内，可能是医疗保健和社会的灾难性成本。许多医院 全世界都经历了由多种耐药性引起的感染爆发（MDR） 铜绿假单胞菌，baumannii和克雷伯氏菌肺炎。所有这些 病原体是六个最高优先级危险细菌的IDSA“命中列表” 紧急注意发现新的抗生素。使用多霉菌素（即结肠菌素和多粘蛋白B） 作为由这些非常有问题的革兰氏阴性引起的感染治疗的“最后一线” 病原体。不幸的是，多碳素的临床实用性受到其肾毒性的阻碍 由于药代动力学局限性，针对肺部感染的效率差。很遗憾， 最近已经报道了质粒传播对多粘蛋白的抗性。从本质上讲，多粘蛋白 抵抗意味着完全缺乏治疗致命感染的抗生素 通过这些革兰氏阴性细菌。显然，迫切需要开发新的抗生素。 所有这三个革兰氏阴性细菌都是该项目的重点。研究设计：建筑物 在过去17年来我们系统的多氧化剂药理学研究中， 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，以合理发展新颖，更安全的多粘蛋白样脂肪肽 靶革兰氏阴性的“超级细菌”，包括抗多氧素的分离株。具体目的是： （1）使用我们建立的脂蛋白化学平台来设计，合成 微生物学评估了大约300种针对MDR K的新型脂肽。 Pneumoniae，P。eruginosa和A. Baumannii； （2）进行主要候选人选择 基于动物模型中的急性毒性，效率和肾毒性，以及麦克风 扩展的临床分离株面板。 AIM 2完成后，铅候选脂肪肽和A 将选择备份以进一步开发（特定目标4）。 （3）阐明机制 使用系统的抗菌活性和肾毒性的类似于脂肪肽 药理学和化学生物学。这些机械研究将改善我们的SAR/STR模型，并 受益于IND申请； （4）开发领先候选人（和备用）以索引 基于对稳定性，毒性，PK和PK/PD的评估的研究 啮齿动物模型。特定目标4的结果还将提供基本的效率和毒性 数据以支持未来的辅助研究。即使它超出了此RFA的范围，我们还是 非常热情的是，确定的主要候选人将被带入与 REMPEX-MEDCO的财政支持。意义：我们的创新提议将发展 急需的更安全，更有效的多碳酸酯来抵消当前的全球健康危机 由革兰氏阴性的“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

Inwardly rectifying potassium channels mediate polymyxin-induced nephrotoxicity.

• DOI: 10.1007/s00018-022-04316-z
• 发表时间: 2022-05-15
• 期刊: Cellular and molecular life sciences : CMLS