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文献精选 > 近年高分"合成生物学"研究（IF≥30，近5年）

Global health perspectives on antibacterial drug discovery and the preclinical pipeline. ​

文献信息 ​

DOI10.1038/s41579-025-01167-w
PMID40148602
期刊Nature reviews. Microbiology
影响因子103.3
JCR 分区Q1
发表年份2025
被引次数5
关键词抗菌药物, 耐药性, 临床管道, 新型化合物, 全球健康
文献类型Journal Article, Review
ISSN1740-1526
页码474-490
期号23(8)
作者Ursula Theuretzbacher, Ravindra P Jumde, Alan Hennessy, Jennifer Cohn, Laura J V Piddock

一句话小结 ​

抗菌耐药性是全球性挑战，当前临床研发主要集中在已知抗生素衍生物，而新型药物的前临床研发则展现出多样性与创新性，这些药物靶向多种生物合成途径，若成功开发将有望解决广泛感染问题。然而，现有研发管道仍面临高淘汰率的挑战，难以满足全球健康需求，尤其是在低收入国家。

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抗菌药物 · 耐药性 · 临床管道 · 新型化合物 · 全球健康

摘要 ​

抗菌耐药性是一个全球性挑战，需要协调一致的国际应对措施。目前的临床研发管道主要由已确立的抗生素类别的衍生物组成，而发现和前临床研发管道则呈现多样化和创新性，包括与现有抗生素无交叉耐药的新型直接作用药物。这些新化合物靶向的途径包括脂蛋白合成、脂多糖生物合成及运输、外膜组装、肽聚糖生物合成、脂肪酸生物合成和异戊二烯生物合成。如果这些药物能够开发成为安全、有效且价格合理的药物，它们将能够解决全球范围内的广泛感染问题，使大量患者受益，而不受地理限制。然而，诸如间接作用或病原体特异性治疗的策略可能仅能惠及小规模的患者群体，主要集中在拥有先进医疗系统和诊断基础设施的高收入国家。尽管前景乐观，发现和前临床研发管道仍然不足以抵消早期药物创新中典型的高淘汰率，也难以满足全球健康需求。

英文摘要 ​

Antibacterial resistance is a global challenge that requires a coordinated international response. The current clinical pipeline largely consists of derivatives of established antibiotic classes, whereas the discovery and preclinical pipeline is diverse and innovative including new direct-acting agents with no cross-resistance with existing antibiotics. These novel compounds target pathways such as lipoprotein synthesis, lipopolysaccharide biosynthesis and transport, outer membrane assembly, peptidoglycan biosynthesis, fatty acid biosynthesis and isoprenoid biosynthesis. If these agents can be developed into safe, effective and affordable drugs, they could address a broad range of infections worldwide, benefiting large patient populations without geographical limitations. However, strategies such as indirect-acting or pathogen-specific treatments are likely to benefit small patient groups, primarily in high-income countries that have advanced health-care systems and diagnostic infrastructure. Although encouraging, the discovery and preclinical pipeline remains insufficiently robust to offset the high attrition rates typical of early-stage drug innovation and to meet global health needs.

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主要研究问题 ​

  1. 当前的抗菌药物研发中，如何平衡新药物的创新性与安全性？
  2. 针对不同地区的抗菌药物需求，是否存在针对性开发的策略？
  3. 在抗菌药物的临床试验阶段，如何提高早期创新药物的成功率？
  4. 预临床阶段的抗菌药物开发中，哪些新靶点显示出最有前景的研究方向？
  5. 如何评估新型抗菌药物对抗药性细菌的有效性与临床应用的可行性？

核心洞察 ​

研究背景和目的 ​

抗菌耐药性是全球面临的重大挑战，需要国际社会的协调应对。目前的临床管道主要由已建立的抗生素类别的衍生物组成，而发现和临床前管道则更加多样化和创新，旨在开发新的直接作用药物，这些药物与现有抗生素没有交叉耐药性。

主要方法/材料/实验设计 ​

研究中探索了新型抗菌化合物，这些化合物针对多个关键生物合成途径。主要的技术路线如下：

Mermaid diagram

关键结果和发现 ​

  • 新发现的化合物针对多个生物合成途径，显示出潜在的抗菌活性。
  • 这些新型化合物在安全性、有效性和可负担性方面具有开发潜力。
  • 直接作用药物有望解决全球范围内的广泛感染问题，尤其是惠及大规模患者群体。

主要结论/意义/创新性 ​

  • 尽管新药物的发现和临床前研究展现出希望，但当前的管道仍不足以抵消早期药物创新中典型的高淘汰率。
  • 这些新型化合物的成功开发可能为全球健康需求提供重要解决方案，特别是在抗菌耐药性日益严重的背景下。

研究局限性和未来方向 ​

局限性未来方向
发现和临床前管道的稳健性不足加强早期阶段药物创新的支持和投资
主要受益于高收入国家的策略开发适用于低收入国家的治疗方案
高淘汰率影响新药物的市场化促进国际合作以加速新药物的开发

未来的研究应集中在加强药物发现的管道，以应对抗菌耐药性带来的挑战，并确保新型抗菌药物能够惠及全球不同经济水平的患者。

参考文献 ​

  1. Antimicrobial Resistance in the Global Health Network: Known Unknowns and Challenges for Efficient Responses in the 21st Century. - Teresa M Coque;Rafael Cantón;Ana Elena Pérez-Cobas;Miguel D Fernández-de-Bobadilla;Fernando Baquero - Microorganisms (2023)
  2. Antibiotic Resistance: Moving From Individual Health Norms to Social Norms in One Health and Global Health. - Sara Hernando-Amado;Teresa M Coque;Fernando Baquero;José L Martínez - Frontiers in microbiology (2020)
  3. The scope of the antimicrobial resistance challenge. - Iruka N Okeke;Marlieke E A de Kraker;Thomas P Van Boeckel;Chirag K Kumar;Heike Schmitt;Ana C Gales;Silvia Bertagnolio;Mike Sharland;Ramanan Laxminarayan - Lancet (London, England) (2024)
  4. Global antimicrobial resistance: a system-wide comprehensive investigation using the Global One Health Index. - Nan Zhou;Zile Cheng;Xiaoxi Zhang;Chao Lv;Chaoyi Guo;Haodong Liu;Ke Dong;Yan Zhang;Chang Liu;Yung-Fu Chang;Sheng Chen;Xiaokui Guo;Xiao-Nong Zhou;Min Li;Yongzhang Zhu - Infectious diseases of poverty (2022)
  5. Socioeconomic disparities in the prevalence of multidrug resistance in Enterobacterales. - Dylan R Brown;Heather I Henderson;Laura Ruegsegger;James Moody;David van Duin - Infection control and hospital epidemiology (2023)
  6. Investigating the impact of poverty on colonization and infection with drug-resistant organisms in humans: a systematic review. - Vivian Alividza;Victor Mariano;Raheelah Ahmad;Esmita Charani;Timothy M Rawson;Alison H Holmes;Enrique Castro-Sánchez - Infectious diseases of poverty (2018)
  7. The contribution of human conflict to the development of antimicrobial resistance. - Scott J C Pallett;Sara E Boyd;Matthew K O'Shea;Jessica Martin;David R Jenkins;Emma J Hutley - Communications medicine (2023)
  8. Association between antibiotic resistance and increasing ambient temperature in China: An ecological study with nationwide panel data. - Weibin Li;Chaojie Liu;Hung Chak Ho;Lin Shi;Yingchao Zeng;Xinyi Yang;Qixian Huang;Yi Pei;Cunrui Huang;Lianping Yang - The Lancet regional health. Western Pacific (2023)
  9. Exploiting genomics for antimicrobial resistance surveillance at One Health interfaces. - Dishon M Muloi;Elita Jauneikaite;Muna F Anjum;Sabiha Y Essack;David A Singleton;Mitchelle R Kasudi;Matthew J Wade;Beverly Egyir;Jamie G Nunn;Janet T Midega;Sharon J Peacock;Nicholas A Feasey;Kate S Baker;Ruth N Zadoks; - The Lancet. Microbe (2023)
  10. Expanding antibiotic, vaccine, and diagnostics development and access to tackle antimicrobial resistance. - Ramanan Laxminarayan;Isabella Impalli;Radha Rangarajan;Jennifer Cohn;Kavi Ramjeet;Betsy Wonderly Trainor;Steffanie Strathdee;Nithima Sumpradit;Daniel Berman;Heiman Wertheim;Kevin Outterson;Padmini Srikantiah;Ursula Theuretzbacher - Lancet (London, England) (2024)

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