Curated Papers > In recent years, high-impact research in "Synthetic Biology" (IF≥30, past 5 years)

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

Literature Information

DOI	10.1038/s41579-025-01167-w
PMID	40148602
Journal	Nature reviews. Microbiology
Impact Factor	103.3
JCR Quartile	Q1
Publication Year	2025
Times Cited	5
Keywords	Antibacterial drug discovery, clinical pipeline, antibacterial resistance, novel compounds, global health
Literature Type	Journal Article, Review
ISSN	1740-1526
Pages	474-490
Issue	23(8)
Authors	Ursula Theuretzbacher, Ravindra P Jumde, Alan Hennessy, Jennifer Cohn, Laura J V Piddock

TL;DR

This research addresses the critical issue of antibacterial resistance by highlighting the need for innovative drug discovery beyond existing antibiotic classes, focusing on new direct-acting agents that target various bacterial biosynthesis pathways. While these novel compounds hold promise for treating a wide range of infections globally, the current pipeline remains inadequate to fully address the urgent demands of global health due to high attrition rates in drug development.

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Antibacterial drug discovery · clinical pipeline · antibacterial resistance · novel compounds · global health

Abstract

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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Primary Questions Addressed

1. What are the key challenges faced in the transition from preclinical discovery to clinical trials for novel antibacterial agents?
2. How do current antibacterial drug discovery strategies differ between high-income and low-income countries?
3. What role do global health organizations play in facilitating the development of new antibacterial drugs?
4. How can the integration of new technologies, such as artificial intelligence, improve the antibacterial drug discovery process?
5. What specific pathways targeted by novel antibacterial compounds show the most promise for future drug development?

Key Findings

Research Background and Objectives

Antibacterial resistance poses a significant global health challenge, necessitating an international collaborative response. The primary objective of the study is to evaluate the current state of antibiotic discovery and development, focusing on innovative compounds that could effectively combat resistant bacterial strains.

Main Methods/Materials/Experimental Design

The study analyzes the current clinical and preclinical pipelines of antibacterial agents. It emphasizes the need for novel direct-acting agents that do not exhibit cross-resistance with existing antibiotics. The compounds under investigation target various critical bacterial pathways, including:

• Lipoprotein synthesis
• Lipopolysaccharide biosynthesis and transport
• Outer membrane assembly
• Peptidoglycan biosynthesis
• Fatty acid biosynthesis
• Isoprenoid biosynthesis

The following flowchart summarizes the technological approach taken in this research:

Key Results and Findings

• The clinical pipeline predominantly consists of modified existing antibiotics, while the preclinical pipeline showcases a diverse range of innovative compounds.
• Novel agents targeting specific bacterial pathways could potentially offer solutions to a wide array of infections, thus benefiting large patient populations globally.
• The effectiveness of these agents hinges on their development into safe, effective, and affordable medications.

Main Conclusions/Significance/Innovation

The study concludes that while the discovery of new antibacterial agents is promising, the existing preclinical pipeline is not sufficiently robust to overcome the high attrition rates commonly associated with early-stage drug development. The potential of novel compounds to address global health needs is significant, particularly for populations in low- and middle-income countries, provided that these drugs can be developed and distributed effectively.

Research Limitations and Future Directions

• Limitations: The current pipeline is insufficiently equipped to meet the global health demands due to high attrition rates and the limited scope of current strategies, which often cater to smaller patient groups in wealthier nations.
• Future Directions: There is a critical need for enhanced investment in research and development of novel antibiotics, focusing on direct-acting agents and broad-spectrum efficacy. Additionally, strategies should be developed to ensure that these innovations are accessible and applicable to diverse healthcare settings worldwide.

Aspect	Current Status	Future Direction
Clinical Pipeline	Predominantly established derivatives	Focus on novel direct-acting agents
Preclinical Pipeline	Innovative but insufficiently robust	Strengthen development strategies
Global Health Impact	Limited by current treatment strategies	Broaden access and applicability
Research Investment	Insufficient	Increase funding for antibiotic R&D

References

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)

Literatures Citing This Work

1. Pentamidine inhibition of streptopain attenuates Streptococcus pyogenes virulence. - Keya Trivedi;Christopher N LaRock - Microbiology spectrum (2025)
2. Challenges of Carbapenem-Resistant Enterobacteriaceae in the Development of New β-Lactamase Inhibitors and Antibiotics. - Pierre Leroux;Charleric Bornet;Jean-Michel Bolla;Anita Cohen - Antibiotics (Basel, Switzerland) (2025)
3. Biomaterials mediated 3R (remove-remodel-repair) strategy: holistic management of Helicobacter pylori infection. - Tinglin Zhang;Yating Zheng;Tielou Chen;Yuankai Gu;Yingli Gong;Dewei Wang;Zhaoshen Li;Yiqi Du;Li Zhang;Jie Gao - Journal of nanobiotechnology (2025)
4. Identification of novel N-benzyloxy-amino acid hydroxamates as inhibitors of the virulence factor LasB from Pseudomonas aeruginosa. - Riccardo Di Leo;Enrico Crispino;Doretta Cuffaro;Giuseppantonio Maisetta;Andrea Bertacca;Marta Bianchi;Giovanna Batoni;Imin Wushur;Fatema Amatur Rahman;Jan-Olof Winberg;Ingebrigt Sylte;Armando Rossello;Elisa Nuti - RSC medicinal chemistry (2025)
5. Efflux-Mediated Resistance in Enterobacteriaceae: Recent Advances and Ongoing Challenges to Inhibit Bacterial Efflux Pumps. - Florent Rouvier;Jean-Michel Brunel;Jean-Marie Pagès;Julia Vergalli - Antibiotics (Basel, Switzerland) (2025)

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