The global preclinical antibacterial pipeline

Abstract

Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of non-traditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work, focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.

Fig. 1. Overview of the preclinical antibacterial pipeline.

We identified 314 research and development institutions and 407 preclinical projects. The projects were categorized according to their main effect on bacteria into the following groups: direct-acting agents, antibodies and vaccines, phages and phage-related products, microbiota-modulating therapies, antivirulence approaches, potentiators of direct-acting drugs, repurposed drugs, immunomodulators or others. The high diversity of approaches provided is innovative but carries high translational risks.

Fig. 2. Type and location of institutions that carry out preclinical antibacterial development.

a | The large majority of institutions involved in the preclinical discovery and preclinical development of antibacterials are small and medium-sized enterprises (255 of 314 institutions in total). Academic institutions, large companies, non-profit institutions and public–private partnerships are comparatively under-represented. b | More than half of the small and medium-sized enterprises are located in North America, followed by Europe as the second most prominent continent. The European countries with five or more companies are the United Kingdom, France, Switzerland, Denmark and the Netherlands.

Fig. 3. Antibacterial approaches, development phase, indications and routes of administration in the preclinical pipeline.

a | Fewer than half of the projects (187, 46%) involve direct-acting antibiotics, 33 projects involve phages or phage-derived peptides that affect bacteria directly, 33 involve agents that target virulence factors, 29 involve antibodies and antibody–drug conjugates, 27 involve antibacterial vaccines, 32 involve potentiators of another antibiotic, 21 involve microbiota-modulating therapies, 15 involve repurposed non-antibiotics or antibiotics that have not been used in systemic bacterial infections of current interest before, 12 involve immunomodulators and 18 others could not be classified in the above classes, such as nanoparticles to support the elimination of pathogens. b | Most institutions that conduct preclinical antibacterial research and development are based in Europe and North America. Projects are relatively evenly distributed between the hit-to-lead, lead optimization and preclinical development phases with clinical trial authorization (CTA)- and investigational new drug application (IND)-enabling studies with a trend towards relatively more projects in the early phase in North America and more projects in the later phases in Europe. c | Although the planned indications cannot be defined for all preclinical projects, the ones that have a planned indication already reflect the WHO priority list of pathogens for which new antibiotics are needed, such as infections with no or few available treatment options and that currently cause substantial morbidity and death, and/or are difficult to treat. d | Most of the agents for which the route of administration has already been defined will be applied parenterally (mostly intravenously and in case of vaccines also intramuscularly). Fewer projects will use oral administration (for systemic treatment, in a few projects this is combined with intravenous treatment), inhalation, local administration (mostly non-absorbable oral administration) and topical formulation for the skin.

Fig. 4. Approaches and spectrum of preclinical direct-acting, small-molecule antibacterials.

a | Direct-acting small molecules in the preclinical antibiotic pipeline are derivatives of ‘old chemical classes’. This group includes β-lactams and other penicillin-binding protein (PBP) inhibitors, fluoroquinolones, novel bacterial topoisomerase inhibitors (NBTIs), aminoglycosides, polymyxins and macrolides. Most direct-acting antibacterials represent new chemical classes and/or have new targets. These small molecules include large groups of synthetic and natural antimicrobial peptides, natural products and inhibitors of LpxC, the first dedicated enzyme in lipid A synthesis. b | Most direct-acting small molecules target Gram-negative bacteria (either with a broader Gram-negative spectrum or pathogen specific). There are fewer molecules aimed at Gram-positive bacteria or with a broad spectrum against both Gram-negative bacteria and Gram-positive bacteria. The numbers for Neisseria gonorrhoeae, Clostridioides difficile and Mycobacterium tuberculosis are shown separately.

Fig. 5. Phages and phage-derived therapeutics, microbiota-modulating approaches and antivirulence approaches in the preclinical pipeline.

a | The most commonly pursued approaches for phage therapy are phage cocktails (either natural phages or engineered phages), engineered phage endolysins and phages that are used as carriers for antibacterial payloads. b | The phages and phage-derived proteins in preclinical development target a large variety of different pathogens and are usually pathogen specific. c | Microbiota-modulating therapies are mainly engineered probiotics or selected natural bacterial strains from a healthy microbiota. We have also included phages as a carrier of antibacterial payloads that specifically manipulate the microbiota in this category. Other microbiota-modulating approaches include use of antibacterial compounds against specific bacteria in the microbiota, antibiotic inactivators in the gut and absorbers of bacterial toxins in the gut, and faecal microbiota transplants (FMT). d | The spectrum of antivirulence compounds is diverse and focuses on Pseudomonas aeruginosa, Enterobacteriaceae spp., Staphylococcus aureus and Clostridioides difficile or, less commonly, is broad.