and development of
new antibiotics and
NADP R&D Focus
The aim of research within the RDA is to deliver and accelerate the development of new bioactive compounds and alternatives to antibiotics aimed at curing infectious diseases caused by antibiotic-resistant bacteria. Genome sequencing and the resulting discovery of numerous previously unseen biosynthetic gene clusters and the advent of innovative engineering tools, such as CRISPR-Cas9 and large-scale gene and protein synthesis, have revolutionised the life sciences. Also it is becoming increasingly clear that host immune mechanisms are involved in the curative response to antibiotic treatment in case of chronic bacterial infections. Together, these technological and scientific advances have opened new opportunities to search for novel antibiotics and alternative therapies to treat bacterial infections in both humans and animals.
Reflective of the expertise and research excellence in the Netherlands, three focus areas are identified within the NADP that aim to decrease our dependence on last resort antibiotics:
- New antibiotic molecules;
- New alternative therapeutics;
- Clinical infrastructure.
The focus areas enable NADP in its support of collaborations between public and private organisations aimed at finding and accelerating the development of new antibiotics and alternative therapies. This RDA presents the current strategic focus of NADP activities, but it also recognises that R&D is a dynamic process and new centers and expertise will develop.
1. New antibiotic molecules
There is a need to identify and introduce novel antibiotics that can by-pass the current resistance mechanisms, to alleviate our dependency on the few antibiotics of last resort that are currently available. Antibiotic resistance is dependent on the chemical class and the mechanism of action of the antibiotic, thus new antibiotics must preferably affect novel targets and/or have sufficient structural novelty. Ideally, an antibiotic has multiple targets that are essential to the target cell, possibly including non-protein-based targets. In both cases there is a significantly lower chance of the occurrence of resistance.
The overall objective of focus area ‘New antibiotic molecules’ is to identify and optimize novel antibiotics against Gram-positive and Gram-negative pathogenic bacteria, based on novel, preferentially multiple, or non-protein based targets.
from the dawn of the antibiotic era to present day, excellence in microbiology has underscored the Dutch contribution to antibiotics research and development. From historic contributions by van Leeuwenhoek, Beyerinck, and Kluyver to current dedicated microbiology centers focussing on identification of new antibiotics via isolation of novel molecules from actinomycetes (van Wezel (LU, NIOO-KNAW)), the largest fungal collection in the world (Westerdijk Fungal Biodiversity Institute), and a large collection of Bacilli with high antimicrobial potential (Kuipers (RUG)). Innovative biotechnology approaches are thereby developed to enable and/or enhance the production of antibiotics and derivatives (van Wezel (LU), Kuipers (RUG)). Furthermore, an internationally renowned research base in bacterial membrane biogenesis including bacterial protein transport is available and being exploited for the discovery of novel antibiotics (Driessen (RUG), Bitter (VU), Tommassen (UU)). The past decade has also witnessed the continued merging of the fields of biology and chemistry - chemical biology - as related to the pursuit of new antibiotics. Aside from providing new tools for the discovery of novel antibiotics, such as the design of activity-based probes to selectively isolate antibiotics (Overkleeft and van der Stelt (LU), (RUG)), chemical biology approaches can also be applied to understanding the mechanisms of action of novel antibiotics and the mechanisms by which pathogenic bacteria develop antibiotic resistance (UU, RUG, UMCG). The focus in chemical biology lies in characterisation and adaptation of antimicrobial compounds (Martin, van Wezel (LU), Kuipers, Minaard (RUG)). Furthermore, strong bioinformatics expertise exists, and the antiSMASH algorithm developed by Medema (WUR) is the most used software for the identification and analysis of biosynthetic gene clusters worldwide. Microbial ecology is an important new field in drug discovery, that harnesses natural signals and eliciting conditions to activate biosynthetic gene clusters that are inactive under routine screening conditions (van Wezel (LU), Raaijmakers (NIOO-KNAW)). Variants of naturally occurring antibiotics are engineered via molecular genetics approaches (Kuipers (RUG)). Elucidating antibiotic mechanisms of action and identification of un(der)exploited targets. Application of activity-based probes (VU, UvA, LU). Important supporting technologies include organs-on-a-chip in which the Netherlands have a leading position (Clevers (Hubrecht-KNAW), Hankemeier (LU) and Mummery (LUMC)).
The Dutch chemical community is extremely strong and has a reputation for delivering world-class innovation as evidenced by a recent Nobel Prize. Synthetic chemistry (Rutjes (KUN), Martin (LU), Feringa (RUG), Breukink (UU)) and innovative concepts (i.e. light-activated antibiotic molecules; Feringa (RUG)) aid in the design of novel structures and libraries and are reflective of excellence in their application to antibiotics. Moreover, synthetic biology approaches have generated large libraries of novel antimicrobial peptides tested by novel high-throughput screening methods, yielding new drug candidates (Kuipers, RUG).
2. New alternative therapeutics
A complementary strategy to the development of new antibiotics is the development of alternative modalities, that can either eliminate bacteria without selecting for novel resistance traits, or that modulate the immune response of the host during (or before) infection. Such strategies should be based on mechanisms of action not yet used by existing antibiotics or whose delivery mechanisms are not (or at least less) susceptible to evolutionary resistance pressure, or on better understanding of the innate and humoral immune response to bacterial infections caused by species creating current and future treatment problems because of AMR. The overall objective of focus area ‘New alternative therapeutics’ is to develop strategies that are targeted towards establishing and/or boosting host immunity as well as reduction of pathogen burden by means of therapies other than broad-spectrum antibiotics.
The use of preventive vaccination to boost host immune responses to clear or to accelerate clearance of the bacterial infection is a potent strategy. Research in vaccine technology and vaccine design dates back to 1950 when the Netherlands introduced the National Immunization Program. It has led to strong research communities in infection biology, microbiology, and innate and adaptive immunology. Particularly the understanding and design of immunomodulatory and anti-inflammatory therapy are a primary strength in the Netherlands (van der Poll (AMC), Rooijakkers (UMCU), van Strijp (UMCU), Haagsman (UU)). Moreover, the ground-breaking concept of trained immunity foreseen to aid in the design of future vaccine strategies was established by Dutch researchers (Netea (RUMC)). To tackle intracellular infections novel vaccination strategies (mostly in tuberculosis) and host-directed therapy (HDT) are being pioneered in the Netherlands. The latter attempts to reprogram the host immune system by pharmacological and chemical-genetic manipulation. Importantly, HDT-driven manipulation of host signalling pathways may be effective also against drug-resistant bacteria and help to restore host control of infection in metabolically perturbed cells. Promising compounds and host target molecules for HDT against MDR-TB and Salmonella have been identified by research groups in the Netherlands working in the field of chemical immunology (Ovaa (LU), Neefjes (LUMC), Ottenhoff (LUMC)). The Netherlands have also pioneered in developing microbiomes for host protection, and in particular to treat infections with Clostridium difficile, using faecal transplants (Kuijper (LUMC)), whereby a faecal transplant bank has been set up (Dutch Donor Feces Bank, LUMC).
Antimicrobial host-derived peptides can kill bacteria rapidly. They function as first line of defence in animals and humans. In addition to antimicrobial activity they also have the ability to stimulate the host’s immune system and in this way indirectly disable microorganisms. Research groups in the Netherlands are leading experts in the field of unravelling the working mechanisms of antimicrobial host-derived peptides (Nibbering (LUMC), Kuipers (RUG), Haagsman (UU), Zaat (AMC)). In addition, an excellent infrastructure in peptide and protein chemistry and synthesis is available (Drijfhout (LU), Heck (UU), Gros (UU)). Another antimicrobial strategy based on the power of the host’s immune system is to combat resistant bacteria via antibody-based therapies. The so-called therapeutic vaccines based on human monoclonal antibodies allow specific targeting of certain bacteria without affecting the host microbiome and thus reducing the risk for antibiotic resistance development. Furthermore, antibodies act immediately and require only basic immune functions that are often retained even in immunocompromised patients. With world-leading academic (Rooijakkers (UU), Parren (LUMC)) and industrial (van de Winkel (Genmab)) experts in antibody discovery, antibody biology research, and antibody engineering the Netherlands is at the forefront of this fast-moving field. Finally, development of bacteriophage technologies and research into the clinical benefits of phage therapy show potential as renewed solutions for antimicrobial therapy (Bonten (UMCU), Brouns (TUD), Struijs (EMC)).
3. Clinical infrastructure
A major challenge in the antibiotics pipeline is how to bring developed antibiotics and alternative therapeutics into the clinic. The pathway of resistance investigation and from hit to lead is a long one. The time needed for clinical evaluation of promising antibacterial compounds (from phase 1 to phase 3 trials) is generally between 5 and 10 years. The Netherlands includes state-of-the-art ‘Clinical Infrastructure’ that aims to support the clinical development of antibiotics and alternatives and to improve the efficiency of these difficult (and thus expensive) trials.
Clinical trials infrastructure
the European Federation of Pharmaceutical Industrial Associations and IMI have created the New Drugs for Bad Bugs program. An important goal is to create a high-quality clinical and laboratory trial network in Europe to optimize clinical trials with new antimicrobial agents. With a managing entity and coordinator in the Netherlands, the Dutch are leading the development of this clinical trial network COMBACTE (Bonten (UMCU)).
the Netherlands is home to a number of groups developing cutting edge (predictive) methods for how well a given compound might behave as a drug. Such technologies have the power to greatly benefit antibiotics and alternatives research by accelerating the process by which early stage lead compounds become clinical candidates. Importantly, such models also have the potential to reduce the need for animal testing in preclinical evaluation of large numbers of candidate compounds. Particularly exciting technologies being developed and applied in the Netherlands today include organs-on-a-chip (Clevers (KNAW-Hubrecht), Hankemeier (LU), Mummery (LUMC)), and zebrafish and other infection models (Spaink & Meijer (LU), Bitter (VUmc)).
4. Industry R&D initiatives
Within the Netherlands, industrial expertise required in the complex process of bringing an initial discovery of an antibiotic hit, through lead and candidate drug development, towards phase I and II clinical trials is available. A complete pipeline of contract research organizations covering essential steps in this process provide hit-to-lead and lead-to-candidate screening assay services (i.e. cytotoxicity), ADME/DMPK (absorption, distribution, metabolism, and excretion/drug metabolism and pharmacokinetics) modelling, chemical synthesis and medicinal chemistry, and in vivo testing. Examples are Pivot Park screening Center and Syncom, both partner in the European Lead Factory program of IMI, Mercachem and Triskelion.
With respect to biotechs developing new antibiotics and alternative therapies, the Netherlands is home to a growing number of small start-ups as well as Europe’s largest biotech Genmab developing antibody-based technologies which can be applied in a variety of indications, including bacterial infections. Also based in the Netherlands is Micreos that develops endolysin- and phage technology enabling targeted killing of pathogenic bacteria, for which the company was chosen as having one of Europe's ten most impactful innovations in 2017. Many major human pharma companies (Merck Sharp & Dohme (MSD), GlaxoSmithKline, Johnson & Johnson, AstraZeneca, etc.) as well as veterinary pharma companies (Zoetis, Boehringer Ingelheim, and MSD Animal Health) have strong alliances to Dutch scientists and invest in collaborative antibiotic and alternative therapies programmes. In total, 15 companies participate and invest in the nationwide NACTAR programme that aims to bring new antibiotics and alternative therapies into pre-clinical development between 2018-2023.
NADP will be closely involved in setting up further research and connecting the industry.