Network T&CM alternatives for antibiotics worldwide: Global Initiative for Traditional Solutions to Antimicrobial Resistance (GIFTS-AMR)

Traditional and Complementary Medicine (T&CM) is often used in both animal and human healthcare and may contribute to reducing inappropriate antibiotic use (e.g. as part of delayed prescription strategies (human healthcare) or as alternative prevention or treatment (e.g. for uncomplicated acute infections in both human and animal healthcare).

Ongoing project

However, there is as yet no global overview or network of research institutes and researchers working in this area and no broadly supported research agenda on T&CM alternative for antibiotics. We therefore aim to build such a network, in order to maximize exchange between research institutes, collaboration on projects and funding activities and to develop research agendas with sufficient support.

Aims:

  • To develop a global “Traditional Solutions to Antimicrobial Resistance” network by mapping and connecting the research fields, research institutes, infrastructures and researchers in human and animal healthcare involved in research on T&CM
  • To develop research agendas starting with at least one to three prioritized indications both in human and veterinary healthcare
  • To prepare grant proposals for research projects and the continuation of the network after the JPIAMR project
  • To communicate to relevant stakeholders the existence, activities and output (e.g. research agendas, website) of the Network, both online (report on website, webinars) and during an (online) international conference

Activities:

  • Plenary and working group meetings: two ‘live’ meetings/ year if possible; otherwise via online video conferences. Telephone or video conference calls.
  • Survey and interviews to collect information of research institutes (e.g. research fields, projects, infrastructure/ networks, databases, available technologies and resources, research capacities and areas that need strengthening)
  • Communication through 3-monthly newsletters, website, congress and webinars

Expected results:

  • A growing globally organized network of Traditional & Complementary Medicine (T&CM) and AMR/ infectious diseases research institutes, researchers in both human and veterinary medicine and global/ regional policy makers
  • A website with accessible information on T&CM, regarding for example research institutes, research fields, projects, infrastructures/ networks, databases,  available technologies and resources
  • A supported research agenda on priority areas for research in both human and veterinary medicine
  • Global communication on the contributions of T&CM (research) to AMR and prevention and treatment of infections
  • Funding and sustainability: the network will facilitate collaboration between institutions with similar interests in order to prepare grant proposals which will enable the research agenda to be implemented, and the network to be sustainable after the end of funding from JPIAMR

Network partners

  • Erik W. Baars, University of Applied Sciences Leiden, Netherlands (Coordinator)

This network includes 33 partners: Network composition (pdf)

Call

Alliance for the Exploration of Pipelines for Inhibitors of Carbapenemases (EPIC Alliance)

EPIC Alliance is composed of 11 members from 7 countries, bringing together experts from the fields of clinical and basic microbiology, infectious diseases, computational biology & chemistry, bioinformatics, biochemistry, translational biology, biophysics, pharmacology, toxicology, veterinary sciences, and epidemiology.

Ongoing project

Carbapenems are among the most potent drugs available to treat bacterial infections that are resistant to other antibiotics. However, several bacteria become resistant to these molecules through the production of enzymes that can break down carbapenems, called carbapenemases. These carbapenemase-producing bacteria threaten our ability to control many infectious diseases across the globe since they render one of the most potent antibiotics ineffective; in addition to frequently being resistant to many other families of antibiotics at the same time. Moreover, there are increasing rates of these carbapenem resistant organisms being reported worldwide. There is thus a great need for strategies to overcome this antimicrobial resistance. One such strategy is the use of carbapenemase inhibitors that might block the action of carbapenemases and could have the potential to reverse the resistance to carbapenems. This approach, though very promising, can be very laborious, time consuming, and costly. Therefore, several groups have relied on computational approaches to detect possible carbapenemase inhibitors. The computational approach is not without its own set of challenges since its success heavily relies on choosing the correct search parameters, algorithms, and databases, in addition to selecting molecules that could successfully pass all the filters before being used in practice.

Within the EPIC Alliance network, we bring together experts from the fields of clinical and basic microbiology, infectious diseases, computational biology & chemistry, bioinformatics, biochemistry, translational biology, biophysics, pharmacology, toxicology, veterinary sciences, and epidemiology spread across seven countries. All members of the network are leading experts in their fields, and with our combined expertise, we will be able to answer the following question: What is the best approach for data mining on carbapenemase inhibitors and how to translate this data into experiments. Specifically, over the course of two years, the consortium will be addressing the following questions, among others that may arise:

  1. What is the best way to predict the carbapenemase inhibiting activity of molecules?
  2. How to target carbapenemases with broad spectrums of activity?
  3. Which parameters should be chosen for the computational data mining for carbapenemase
    inhibitors?
  4. How can we test candidate molecules in-vitro, in-vivo, and through clinical trials?
  5. What is the cost-effectiveness and feasibility of this approach?
  6. Is this approach better than already existing ones?

By answering these questions, we hope to reach a unified strategy for finding and testing these important molecules that can safesafeguard the use of carbapenems and help in the global effort to fight against bacterial resistance.

Network partners

  • Elias Dahdouh, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Spain (Coordinator)
  • Dr. Jesús Mingorance from the Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Spain
  • Dr. Paulino Gómez Puertas from the Centro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Spain
  • Dr. Stefano Lorenzetti from the Istituto Superiore di Sanità (ISS), Italy, in collaboration with Dr. Francesca Spyrakis from the University of Turin, Italy
  • Dr. Thierry Naas from the Université Paris-Saclay, Hôpital de Bicêtre, France
  • Dr. Bogdan Iorga from the Institut de Chimie des Substances Naturelles (ICSN), CNRS,
  • Université Paris-Saclay, France
  • Dr. Nathaniel Martin from the Institute of Biology Leiden, Leiden University, The Netherlands
  • Dr. Joe Rubin from the University of Saskatchewan at Saskatoon, Canada
  • Dr. Luis Martínez-Martínez from the Instituto Maimónides de Investigación Biomédica de
  • Córdoba (IMIBIC), Spain
  • Dr. Thomas Tängdén from the Uppsala University, Sweden
  • Dr. Linda Falgenhauer from the Justus Liebig University Giessen, Germany

Call

JPIAMR Network for Integrating Microbial Sequencing and Platforms for Antimicrobial Resistance (Seq4AMR)

Main Questions/Approach: How can we best identify and promote collaboration and implementation between AMR NGS stakeholders that link the individual fields of (new) NGS technologies, algorithms, quality standards, teaching/training and sequence databanks?

Ongoing project

Answer – By establishing an international and interdisciplinary OneHealth network of public and private experts to take the lead in identifying potential knowledge gaps and solutions. Further, by developing AMR NGS-dedicated quality and teaching/training materials. Finally, by promoting discussion and interactions between AMR NGS stakeholders and other working groups with cross-cutting priorities – including extensive use of JPIAMR VRI.

Objectives:

  1. Promote active collaboration between interdisciplinary OneHealth AMR NGS stakeholders
  2. Identify knowledge gaps and provide solutions to current/future AMR NGS issues
  3. Formulate recommendations on quality and quality materials
  4. Educate AMR NGS stakeholders via interdisciplinary-directed AMR NGS teaching/training materials

Activities:

  1. Dedicated website and access to network materials
  2. Face-to-face network meetings and regular teleconferences (in collaboration with other relevant JPIAMR working groups)
  3. Open access publications and collation of a Seq4AMR Strategic Roadmap
  4. Dedicated interdisciplinary Seq4AMR webinar(s) and course(s)
  5. Dedicated Seq4AMR workshop at a relevant international meeting
  6. Promotion of Seq4AMR and JPIAMR during conferences.

Expected Results:

  1. Establish new OneHealth AMR synergies between international and interdisciplinary experts for knowledge exchange, joint publications grant writing etc.
  2. Identify current knowledge gaps and how to best fill these gaps
  3. Formulate quality recommendations and access to materials
  4. Develop new interdisciplinary AMR teaching/training/ materials
  5. To publish a Seq4AMR Strategic Roadmap
  6. To contribute and strengthen the activities of JPIAMR VRI

Network partners

  • John Hays, Erasmus MC University Medical Center, Netherlands (Coordinator)
  • A. Stubbs, Erasmus MC University Medical Center, Netherlands
  • A. Heikema, Erasmus MC University Medical Center, Netherlands
  • A. van Belkum, BioMérieu France, Craponne, France
  • W. A. Valdivia, Orion Integrated Biosciences (OIB), Kansas, USA
  • Liping Ma, East China Normal University, Shanghai, China
  • E. Kristiansson, University of Gothenburg, Gothenburg, Sweden
  • S. Bruchmann, Cambridge University, Cambridge, UK
  • A. McArthur, McMaster University, Hamilton, Canada (CARD Database)
  • S. Emler, SmartGene GmbH, Lausanne, Switzerland
  • E. Claas, Leiden University Hospital, Leiden, the Netherlands
  • S. Beisken, Ares Genetics GmbH, Vienna, Austria
  • R. Stabler, London School for Hygiene and Tropical Medicine, London, UK
  • A. Lebrand, Swiss Institute of Bioinformatics, Lausanne, Switzerland
  • M. Petrillo, European Commission, Joint Research Centre (JRC), Ispra, Italy
  • S. Capella-Gutierrez, Barcelona Supercomputing Centre (BSC), Barcelona, Spain
  • L. Portell, Barcelona Supercomputing Centre (BSC), Barcelona, Spain
  • B. Grüning, Freiburg Galaxy Team, Freiburg, Germany
  • G. Cuccuru, Freiburg Galaxy Team, Freiburg, Germany
  • C. Carrillo, Canadian Food Inspection Agency, Ottawa, Canada
  • B. Blais, Canadian Food Inspection Agency, Ottawa, Canada
  • B. Gruening, University of Freiburg, Freiburg, Germany
  • W. Meier, University of Freiburg, Freiburg, Germany
  • B. Batut, University of Freiburg, Freiburg, Germany
  • K. Vanneste, Sciensano, Brussels, Belgium
  • J. Bengtsson-Palme, University of Gothenburg, Gothenburg, Sweden
  • T. Naas, Hopital de Bicêtre, Paris, France
  • N. Strepis, Erasmus University Medical Centre (Erasmus MC), the Netherlands
  • A. Rhod Larsen, Statens Serum Institut, Copenhagen, Denmark
  • B. Helwigh, National Food Institute, Lyngby, Denmark
  • H. Hasman, National Food Institute, Lyngby, Denmark
  • R. Hendriksen, National Food Institute, Lyngby, Denmark
  • S. Forslund, Max Delbrück Center for Molecular Medicine, Berlin, Germany 
  • L. Pedro Coelho, Institute of Science and Technology, Fudan University, Shanghai, China
  • A. Patak, Molecular Biology and Genomics Unit, Institute for Health and Consumer Protection, Ispra, Italy
  • M. Querci, Deputy Head of Unit, Joint Research Centre European Commission, Brussels, Belgium
  • G. van den Eede, Head of Unit, Health, Consumer and Reference Materials, European Union, Brussels, Belgium

Call

Fighting antibiotic-resistant superbugs with anti-persister compounds targeting the stringent response (Anti-Persistence)

Pathogenic antibiotic-resistant “superbugs” are increasing at an alarming pace. Persistence to antibiotics favours the emergence of resistance as mutations increasing antibiotic tolerance favour selection of resistance mutations.

Ongoing project

Persisters constitute subpopulations of cells that can withstand bactericidal antibiotics and are considered as a primary source of infections since they are difficult or impossible to eradicate with conventional antibiotics. Persister bacteria are encountered in a variety of chronic pathologies, including cystic fibrosis, pneumonia and tuberculosis.

Thus the impact of persistence on public health is enormous and there is a pressing need to develop treatments to kill persisters. The existence of a causal link between persisters and persistent infections was demonstrated for S. typhimurium, whose survival inside the host relies on ppGpp. Compounds capable of killing persisters could sterilise S. aureus cultures and cured methicillin-resistant S. aureus (MRSA)infected mice. Thus targeting the enzymes that regulate ppGpp is an interesting and unexplored route to develop new antibiotics active against persisters.

This project aims to target key steps in the mechanism of ppGpp synthesis and hydrolysis in a variety of pathogenic bacteria. In an integrative biochemistry, structural and cellular biology based approach we will uncover novel mechanistic aspects of persistence, deliver novel metabolic biosensors for single-cell analysis and methodologies to study persisters in human pathogens, and discover and validate novel compounds with antipersister action.

Project partners

  • Abel Garcia-Pino, Université Libre de Bruxelles, Belgium (Coordinator)
  • Leonardo Pardo, Universitat Autònoma de Barcelona, Spain
  • Ewa Laskowska, University of Gdansk, Poland
  • Olivier Neyrolles, Université de Toulouse, France

Since the discovery of penicillin by Fleming in the late 1920s, antibiotics have revolutionized the field of medicine and human society in general. However, the antibiotic development pipeline dried out in the late 1980s and we have now reached a critical point where many antibiotics are no longer effective against even the simplest infections. In this context, infectious diseases are now the second leading cause of death in the world with 17 million people dying each year from bacterial infections worldwide.

Pathogenic antibiotic-resistant “superbugs” are a particularly problematic emergent global health threat growing at an alarming pace. These superbugs are typically highly antibiotic tolerant and multi-drug resistant. One of the survival strategies of these pathogens is to enter in a seemingly “dormant” state that suspends cell division known as persister state. Disguised as persisters, bacteria become highly tolerant to antibiotics and stress in general, therefore targeting persisters has become one of the modern challenges of microbiology. These non-growing bacteria are encountered in a variety of chronic pathologies, including cystic fibrosis, pneumonia and tuberculosis (TB).

Thus the impact of persistence on public health is thus enormous and there is a pressing need to develop treatments to kill persisters. It has been previously shown that a strategy that addresses the persistence problem is a promising approach in the fight against multi-drug resistant superbugs. Therefore this project aims to target key steps in the mechanisms of pathogenic bacteria to regulate stress that are involved in persistence from integrative biochemistry-, structural and cellular biology-based perspective to discover novel compounds that could lead to the development of new types of antibiotics.

Publications

Call

Design, synthesis and lead generation of novel siderophore conjugates for the detection and treatment of infections by Gram-negative pathogens (SCAN)

There is a strong need for novel, innovative therapeutic solutions for infections caused by Gramnegative pathogens. In addition, there is a lack of tools to diagnose bacterial infections at deep body sites, e.g. on implant surfaces.

Ongoing project

In the project SCAN (Siderophore Conjugates Against Gram-Negatives), we apply a rational design approach to establish a targeting conjugate platform that can be used to both diagnose as well as treat bacterial infections (‘theranostics’ principle). The conjugates are actively transported into bacteria through their iron transport machinery that accepts siderophores as substrates.

This concept has recently been validated clinically and addresses a key issue of Gramnegative pathogens, the impaired translocation into the cell. We will design and synthesise novel siderophores that employ novel central scaffolds and combinations of iron-binding motifs. Those will be coupled with hitherto unexplored effectors: RNA polymerase inhibitors are employed as potent antibiotics, and dioxetane-based chemiluminescent probes will be used for imaging.

As a linkage between siderophore and antibiotic, cleavable, self-immolative linkers (e.g. trimethyl lock) will be constructed. The conjugates will be characterised in cellular assays and in infection models in mice. Their translocation and resistance mechanisms will be investigated by genetic and proteomic methods. The project should yield novel antibiotic lead structures with proven efficacy in vivo.

Project partners

  • Mark Brönstrup, Helmholtz Centre for Infection Research, Germany (Coordinator)
  • Doron Shabat, Tel-Aviv University, Israel
  • Isabelle Schalk, CNRS – Université de Strasbourg, France

Infections caused by multidrug-resistant Gram-negative bacteria result in significant mortality and morbidity worldwide. In line with this, all pathogens that received a ‘critical’ status by the recently established WHO priority list were drug-resistant Gram-negative species. The reasons for limited success of pharmaceutical research programs in the area of antibiotics have been carefully analyzed: the main hurdle is the limited understanding how to get drugs into Gram-negative bacteria. Thus, there is a strong need for novel, innovative drugs against infections caused by Gram-negative pathogens. There is also a lack of tools to diagnose bacterial infections at deep body sites, e.g. on implant surfaces.

In the project SCAN (Siderophore Conjugates Against gram-Negatives), we apply a rational design approach to establish a targeting conjugate platform that can be used to both diagnose and treat bacterial infections (‘theranostics’ principle). The conjugates are actively transported into bacteria through their iron transport machinery that accepts siderophores as substrates. As this resembles the strategy of ancient Trojan warriors, the approach has been named the ‘Trojan Horse Strategy’. This concept has recently been validated clinically, a first drug (Fetroja) has been approved and is available to patients.

We will design and synthesize artificial siderophores that employ novel central scaffolds and combinations of iron-binding motifs. Those will be coupled with hitherto unexplored effectors: RNA polymerase inhibitors are employed as potent antibiotics, and chemiluminescent probes will be used for imaging. As a linkage between siderophore and antibiotic, cleavable, self-immolative linkers will be constructed. The conjugates will be characterized in cellular assays and in animal infection models. Their translocation and resistance mechanisms will be investigated by genetic and proteomic methods.

The project should yield novel antibiotic lead structures as well as activatable bacterial probes with proven efficacy in vivo to detect and treat infections. Taken together, the afforded antimicrobials and moreover the novel theranostics could be tools that allow for strain-specific, potent treatment and monitoring of bacterial infections, addressing a major medical need expressed by the WHO.

Project resources

Call

Development of novel ribosome-targeting antibiotics (RIBOTARGET)

The ribosome is one of the major targets for antibiotics. Multi-drug resistant pathogens are making our current arsenal of ribosome-targeting antibiotics obsolete, highlighting the need for development of new antimicrobial compounds.

Ongoing project

Here we focus on discovering novel ribosometargeting antibiotics with improved activity and selectivity, with chemical scaffolds that target novel sites on the ribosome and different steps of the translation cycle.

Specifically, we propose to (WP1) develop novel aminoglycoside antibiotics with potent antibacterial activity and improved target selectivity to overcome the toxicity that is associated with this clinically important class of antibiotics; (WP2) develop proline-rich antimicrobial peptides as novel antimicrobial agents by taking advantage of available high resolution ribosome structures and their ease of synthesis and modification; (WP34) utilise high-throughput screening to discover compounds with novel chemical scaffolds that have activity against new cellular targets, such as the (WP3) ribosome rescue systems, and (WP4) stringent response pathways in bacteria.

The consortium aims to characterise the mechanism of action of novel antimicrobial agents as well as their in vivo and in vitro efficacy, in particular against Priority 1 pathogens and Mycobacterium tuberculosis.

Project partners

  • Daniel Wilson, University of Hamburg, Germany (Coordinator)
  • C. Axel Innis, Institut Européen de Chimie et Biologie, France
  • Erik Böttger, University of Zurich, Switzerland
  • Vasili Hauryliuk, Umeå University, Sweden
  • Reynald Gillet, Université de Rennes, France
  • Dominik Rejman, The Czech Academy of Sciences, Czech Republic
  • Marco Scocchi, University of Trieste, Italy

Multi-drug resistant pathogens are making our current arsenal of ribosome-targeting antibiotics obsolete, highlighting the need for development of new antimicrobial compounds.

The RIBOTARGET consortium aims to discover novel ribosome-targeting antibiotics with improved activity and selectivity against Priority 1 pathogens and Mycobacterium tuberculosis, with chemical scaffolds that target novel sites on the ribosome and different steps of the translation cycle. This includes development of (i) novel aminoglycoside antibiotics with potent antibacterial activity and improved target selectivity to overcome the toxicity that is associated with this clinically important class of antibiotics; (ii) proline-rich antimicrobial peptides as novel antimicrobial agents by taking advantage of available high resolution ribosome structures and their ease of synthesis and modification, as well as (iii-iv) utilizing high-throughput screening to discover compounds with novel chemical scaffolds that have activity against new cellular targets, such as the (iii) ribosome rescue systems, and (iv) stringent response pathways in bacteria.

To achieve these aims our multi-interdisciplinary RIBOTARGET consortium brings together leading scientists with complementary expertise in microbiology, biochemistry, chemical synthesis and structural biology. This will enable us to characterize the mechanism of action of novel antimicrobial agents as well as their in vivo and in vitro efficacy.

Publications

Call

Restoring E. coli Sensitivity for Antibiotics by blocking TolC-Mediated Efflux (RESET-ME)

Overexpression of efflux pumps is a major factor for drug resistance in Gram-negative bacteria. In E. coli, the AcrAB-TolC efflux pump complex transports antibiotics from the periplasm or cytoplasm into the external medium. As TolC deletion has been shown to result in increased susceptibilities of E. coli to several antibiotics, it may represent an attractive drug target.

Ongoing project

Recently, we have identified the first organic small molecule that effectively blocks TolC function using virtual screening in combination with experimental validation of the in silico hits by surface plasmon resonance (SPR) and electrophysiology studies. Building on these results, we propose to further develop this compound and in parallel to identify and develop novel TolC blockers within an interdisciplinary consortium.

The already known blocker will be progressed in three rounds of optimisation. Each round comprises compound modifications by medicinal chemistry, assessment of TolC binding and blockage using SPR and electrophysiology, various antimicrobial studies and ADMETox profiling. Novel small molecules blocking TolC will be identified and optimised using the same experimental platform, starting with virtual screening for identification of novel compounds targeting TolC. Experimentally validated TolC blockers will be progressed in two rounds of optimisation. Ultimately, this approach will allow to assess TolC target validity for adjuvants in antimicrobial therapies and result in potent TolC blockers that may be further developed into drugs restoring E. coli susceptibility to antibiotics.

Project partners

  • Björn Windshügel, Fraunhofer Institute for Molecular Biology and Applied Ecology, IME, Germany (Coordinator)
  • Mathias Winterhalter, Jacobs University Bremen, Germany
  • Päivi Tammela, University of Helsinki, Finland
  • Aigars Jirgensons, Latvian Institute of Organic Synthesis, Latvia
  • Matteo Ceccarelli, University of Cagliari, Italy

Bacteria have developed several resistance mechanisms against antibiotics. One of these mechanisms involves fast removal of antibiotics from the bacterium. This results in an impaired effect of antibiotics. For this purpose, bacteria use so-called efflux pumps, which are large protein complexes composed of three different components. In E. coli, this complex consists of a pump located in the inner membrane (AcrB),a periplasmic adapter protein (AcrA)and the outer membrane factor TolC.

The aim of our project is to develop molecules that block the outer membrane factor TolCin a way that antibiotics cannot be removed anymore from the bacterium. As a consequence, the efficacy of antibiotics can be improved significantly. In this project, an interdisciplinary team composed of research groups from Germany, Finland, Latvia, and Italy combines different experimental and computational techniques for identification and optimization of efflux pump blockers which sensitize E. colibacteria for antibiotics. If successful, the approach will be applied also to other human pathogenic bacteria.

Project resources

Publications

Call

Development of novel Mycobacterial Tolerance Inhibitors (MTIs) against MDR/XDR tuberculosis (MTI4MDR-TB)

In 2017, WHO published the Global Priority Pathogen lists with the aim to promote research and development of new treatments that are effective against microbes resistant to multiple antibiotics. Among them, multi- and extensively drug resistant Mycobacterium tuberculosis caused 48% of new tuberculosis (TB) cases in some countries in 2016.

Ongoing project

Current regimens for the treatment of TB include a combination of antibiotics developed for their strong efficacy against drug sensitive bacterium. The inadequacies of present TB therapies demand discovery of new agents with unique mechanisms of action to treat Mtb infection. Towards this end, we have discovered and developed a new family of ring-fused 2-pyridones (termed Mycobacterial Tolerance Inhibitors, MTIs) that potently sensitise Mtb to stresses encountered during infection and restores activity to the frontline antibiotic isoniazid (INH) in otherwise INH-resistant Mtb isolates.

Our short-term objectives are to demonstrate preclinical proof-of-concept for MTIs to combat Mtb infection, optimise the current lead MTIs for translation to a therapeutic, and reveal new insights into pathways of drug tolerance and resistance. Our long-term objective is to develop a new orally available antibiotic that improves the current regimens for patients with drug-resistant TB. We will also generate a deeper understanding of the MTI’s mode of action and their potential in synergistic interactions with other drugs. Importantly, we will also study how likely it will be for Mtb to develop resistance to combinations of MTIs and INH and other antibiotics.

Project partners

  • Fredrik Almqvist, Umeå University, Sweden (Coordinator)
  • Camille Locht, University of Lille, CNRS, Inserm, France
  • Tone Tønjum, University of Oslo, Norway
  • Jesús Blázquez, National Center for Biotechnology, CSIC, Spain
  • Christina Stallings, Washington University School of Medicine, USA

In 2017, WHO published the Global Priority Pathogen lists with the aim to promote research and development of new treatments that are effective against microbes resistant to multiple antibiotics. Among them, multi- and extensively drug resistant Mycobacterium tuberculosis caused 48% of new tuberculosis (TB) cases in some countries in 2016. Current regimens for the treatment of TB include a combination of antibiotics developed for their strong efficacy against drug sensitive bacterium. The inadequacies of present TB therapies demand discovery of new agents with unique mechanisms of action to treat Mtb infection. Towards this end, we have discovered and developed a new family of ring-fused 2-pyridones (termed Mycobacterial Tolerance Inhibitors, MTIs) that potently sensitise Mtb to stresses encountered during infection and restores activity to the frontline antibiotic isoniazid (INH) in otherwise INH-resistant Mtb isolates.

Our short-term objectives are to demonstrate preclinical proof-of-concept for MTIs to combat Mtb infection, optimise the current lead MTIs for translation to a therapeutic and reveal new insights into pathways of drug tolerance and resistance. Our long-term objective is to develop a new orally available antibiotic that improves the current regimens for patients with drug-resistant TB. We will also generate a deeper understanding of the MTI’s mode of action and their potential in synergistic interactions with other drugs. Importantly, we will also study how likely it will be for Mtb to develop resistance to combinations of MTIs and INH and other antibiotics.

Project resources

Publications

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Flavodoxin inhibitors to kill resistant bacteria (FLAV4AMR)

This transnational collaboration gathers the expertise and resources required to address lead improvement to the point of producing novel antibiotics ready for clinical trials, and to clarify the overall importance of flavodoxin as a novel drug target.

Ongoing project

The project has two goals:

  1. To culminate the improvement of inhibitors of the flavodoxin from H. pylori, which have shown efficacy against reference and clinical strains (including a clarithromycin-resistant one) and in a mice model.
  2. To determine the relevance of flavodoxin as a novel drug target to fight bacteria which pose problems associated to antimicrobial resistance.

Project partners

  • Javier Sancho, Javier Sancho, Spain (Coordinator)
  • Eliette Touati, Pasteur Institute, France
  • Ultrich E Schaible, Research Center Borstel, Germany
  • Alain Bousquet-Melou, Ecole Nationale Vétérinaire de Toulouse, France

Some bacteria and other microorganisms are pathogens responsible for human infectious diseases. Bacterial infections are commonly fought using antibiotics or, more generally, antimicrobials. the prolonged use (and misuse) of antimicrobials over time to fight human infections has allowed some bacteria to develop molecular mechanism that neutralize antimicrobials. Such bacteria are in practice antimicrobial resistant and constitute a serious global threat to human health. In the European Union, antimicrobial resistance is responsible for 33,000 deaths annually and the costs of medical care and productivity losses are estimated in 1.5 billion euros.

The bacteria Helicobacter pylori (Hp) has been identified by the WHO as one of the pathogens for which it is urgent to find new antibacterial compounds, due to the high incidence of antibiotic-resistant strains along with the fact that half of the world’s population suffers from gastric infections caused by Hp, and because Hp infection constitutes a risk factor for developing gastric cancer. The Spanish-Franco-German project Flavodoxin inhibitors to kill resistant bacteria (FLAV4AMR), has been conceived as a transnational collaboration that brings together all expertise and resources needed to develop new antimicrobial compounds that could enter clinical testing and renew our arsenal against Hp. These novel antimicrobials act by a mechanism different from those of existing broad-range antimicrobials and therefore may be specific against Hp. Moreover they may not damage the beneficial microbiota and thus be useful for a personalize treatment of infectious diseases.

The project is led by Javier Sancho (Biochemistry Professor, and researcher at the University Institute for Research on Biocomputing and Physics of Complex Systems – BIFI). “Our ultimate goal is to develop new flavodoxin inhibitors having significant antimicrobial activity, both for Hp and for other pathogens that present significant problems because of their antibiotic resistance, and that can reach the market within a reasonable time, then, having a high impact on medicine,”

Project resources

Publications

Call

Exploration of the TPP riboswitch as a new target for antibiotics (Explore)

In this project, we will explore the TPP riboswitch as a new drug target for antibiotics for key ESKAPE pathogens (E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, S. aureus) and Streptococcus pneumoniae.

Ongoing project

The TPP riboswitch has already been validated as a drug target, however, potent and drug-like ligands with antibiotic activity are needed as starting points to develop novel strategies for anti-infective treatments. The goal of this proposal is to deliver such compounds. Using an innovative assay technology, we will develop a high-throughput assay that monitors simultaneously transcription efficiency and the regulatory activity of the riboswitch, which is crucial for its action, and use this assay to screen the CZ- and EU-OPENSCREEN libraries of lead-like compounds. The hits obtained will be thoroughly validated and the most promising hits will be optimised to improve their affinity.

The advanced compounds will be evaluated for antibiotic activity against the key ESKAPE pathogens and Streptococcus pneumoniae. We will also assess the broad-spectrum potential of the compounds and carry out mode of action studies to ensure that the compounds act on target. If the TPP riboswitch holds up to its high promises, this project will pave the way for urgently needed new antibiotics.

Project partners

  • Ruth Brenk, University of Bergen, Norway (Coordinator)
  • Petr Bartunek, Institute of Molecular Genetics of the ASCR, Czech Republic
  • Matthias Mack, Mannheim University of Applied Sciences, Germany
  • Gints Smits, Latvian Institute of Organic Synthesis, Latvia
  • Daniel Lafontaine, Université de Sherbrooke, Canada

The antibiotics we are currently using are losing effectiveness due to the emergence of resistant bacteria. Therefore, there is an urgent need to develop new antibiotics. In this project, we aim to develop ligands for an RNA element (a so-called riboswitch), that controls the expression of essential bacterial genes. These ligands can then serve as starting points for drug discovery for future antibiotics.

To reach this goal, we have assembled a team of highly skilled researchers from Norway, the Czech Republic, Latvia, Germany, and Canada. Together, we are developing a test system so that we can screen thousands of molecules for binding to the target. Subsequently, the identified ligands will be optimized to increase their affinity. The advanced compounds will be evaluated for antibiotic activity against the key bacteria for which new antibiotics are urgently needed. We will also carry out mode-of-action-studies to ensure that the compounds act on target as intended. If investigated riboswitch holds up to its high promises, this project will pave the way for urgently needed new antibiotics.

Project resources

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