All Awards

Joleen Masschelein of the VIB-KU Leuven Center for Microbiology in Belgium, with Paul Jensen of the University of California San Diego in the U.S., Lone Gram of Danmarks Tekniske Universitet in Denmark, Gilles van Wezel of Leiden University , Jos Raaijmakers of Netherlands Institute of Ecology, Bart Keijser of Netherlands Organisation for Applied Scientific Research all three in The Netherlands, Olga Genilloud at Medina in Spain and Nigel Mouncey at the Joint Genome Institute in the U.S., will apply ecology-inspired strategies to discover new antibiotics active against multidrug-resistant Klebsiella pneumoniae. The team will combine culture-independent metabolite capture, elicitation-based activation of microbial chemistry, high-throughput microfluidics, multi-omics and synthetic biology to access previously hidden natural product diversity from marine, plant, and human-associated microbiomes. Novel compounds will be prioritized, structurally characterized, and profiled for activity and safety to identify promising antibiotic scaffolds and mechanisms of action.

This grant is funded by The Novo Nordisk Foundation.

Annette von Delft and collaborators Nicole Stoesser, Lizbe Koekemoer, Ed Griffen, Paul Brennan, Frank von Delft, Phil Fowler, and Thomas Lanyon-Hoggat of the University of Oxford in the United Kingdom will utilize their well-established crystallographic fragment screening platform (XChem) and the newly developed Fast Forward Fragments (FFF) platform for rapidly progressing fragment hits into scaffolds, to identify novel small molecule hit series against three validated Klebsiella targets. Based on novel crystallographic fragment screening hits, they will generate novel chemical matter that directly addresses classical compound liabilities, by firstly prioritizing scaffolds that accumulate in efflux-pump expressing Klebsiella/Enterobacterales in design-make-test (DMT) cycles (assessed through a mass spectrometry based assay); secondly, by developing scaffolds by exclusively targeting resistance robust residues within the active site identified through an upfront assessment of target sequence variability; and thirdly by continuously optimizing for broad-spectrum Klebsiella spp. (plus other Enterobacterales) activity. Ultimately, they aim to enable a "ready-to-use", target-based antimicrobial discovery pipeline that can be applied to evaluating novel bacterial targets more broadly.

This grant is funded by The Novo Nordisk Foundation.

Joan Mecsas in collaboration with Bree Aldridge and Ralph Isberg all from Tufts University in the U.S. will develop portable tissue-specific in vivo and in vitro models that will be standardizable to accelerate Gram-negative drug discovery. In parallel, they will create a genetic target screening technology to identify drug-susceptible genes and pathways across a diverse set of multidrug-resistant Klebsiella pneumoniae strains in tissue-specific models. Their approach seeks to mitigate two key challenges to drug discovery: the high degree of bacterial genetic heterogeneity among multidrug-resistant Klebsiella, and the multiple distinct tissue environments inhabited by Klebsiella, both of which can significantly impact drug responses.  The overarching goals are to generate a compendium of pan-targets and dual-pan-targets, which include critical contextual information about conditionality on tissue niche and strain, and to de-risk drug discovery by using tractable tissue-based models for discovery, prioritization, and evaluation of new therapeutics.

This grant is funded by The Novo Nordisk Foundation.

Rebecca Page and her team at the University of Connecticut Health Center in the U.S. are developing a new class of antibiotic to target Klebsiella species. This strategy leverages their recent discovery that key steps in the formation of the bacterial cell wall, peptidoglycan recruitment and crosslinking, occur at different sites in penicillin binding proteins (PBPs). Their team will use an integrated approach combining sophisticated NMR spectroscopy, X-ray crystallography, high-throughput fragment screening, substrate synthesis, biochemistry and biophysics to identify the specific residues in Klebsiella PBPs responsible for peptidoglycan recruitment. They will then identify novel chemical matter that target these sites. This new class of antibiotics is predicted to have an exceptionally high barrier to resistance because mutations that inhibit antibiotic binding will also inhibit substrate recruitment and, in turn, the formation of the bacterial cell wall.

This grant is funded by The Novo Nordisk Foundation.

Gaurav Bhardwaj along with collaborators Joshua Woodward and Frank DiMaio all of the University of Washington in the U.S. will leverage recent advances in deep learning methods to build an AI-enabled platform for designing peptidomimetics and small-molecule inhibitors of essential bacterial proteins. The team will pursue three complementary strategies in parallel to design new antibiotic candidates against Klebsiella pneumoniae. First, they will redesign natural products into more stable, synthetically-accessible peptidomimetics. In parallel, they will use AI-enabled methods to de novo design new direct-acting inhibitors of critical bacterial proteins. Finally, the team will use bioactive macrocyclic peptides to identify potent small molecule inhibitors of bacterial proteins critical for growth and survival. Together, these approaches will establish a broadly applicable platform for the rapidly generating customized antibiotic candidates against a range of targets and bacterial pathogens.

This grant is funded by The Novo Nordisk Foundation.

Ian Gilbert and colleagues at the University of Dundee in the United Kingdom, along with Beverly Egyir of the Noguchi Memorial Institute for Medical Research in Ghana, will integrate microbiology and industrial drug discovery expertise to tackle drug-resistant and hypervirulent Klebsiella. They will screen compounds in infection-mimicking conditions to identify novel chemical start points and drug targets. In contrast to current antibiotic targets which are essential for growth, the team will seek drug targets which cause lethal damage to bacteria when they are in slow or non-growing states typical of infection environments. They will use their integrated drug discovery platform to validate and optimize hits, including testing against global clinical isolates, with the aim of establishing proof of concept for these new series.

This grant is funded by The Novo Nordisk Foundation.

Kim Lewis of Northeastern University in the U.S. will lead a team that will develop an advanced platform to resolve intractable bottlenecks in antibiotic discovery. The focus will be on 30 targets in the cell envelope of Gram-negative bacteria. An AI-based search of genomic libraries for biosynthetic gene clusters associated with these targets produces candidate hits for isolation and also identifies producing taxa for selective capture of soil microbes. Encapsulating single cells from the environment in microdroplets obviates library construction. A pair of differently colored detector strains, susceptible/resistant to a compound hitting the desired target, identifies attractive hits at a test rate of 1,000,000/hour. Uncultured bacteria are incorporated into the screen, and the platform provides access to silent operons. Antibiotics discovered in this project will serve as a starting point for subsequent medicinal chemistry optimization.

This grant is funded by The Novo Nordisk Foundation.

Andrew Edwards, Edward Tate, Matthew Child, Gad Frankel, Paul Freemont, Marko Storch, Alessandra Russo, Mauricio Barahona and Ramon Vilar of Imperial College London, part of the Fleming Initiative, in the United Kingdom, will use novel genomic and proteomic approaches to identify previously unrecognized targets for new anti-Klebsiella therapeutics. In parallel, the team will use high-throughput accumulation assays, physical chemistry, AI/Machine Learning, data science and molecular bacteriology approaches to decipher the chemical rules of small molecule accumulation in Klebsiella cells. Combined, this work will identify new targets and ensure that small molecule inhibitors accumulate at therapeutic concentrations, paving the way for the development of novel antibiotics active against Klebsiella and other Gram-negative priority pathogens.

This grant is funded by The Wellcome Trust.

Paul J. Hergenrother, along with collaborators at the University of Illinois in the US - Rohit Bhargava, William Metcalf, Gee Lau, and Emad Tajkhorshid - will develop tools that will ultimately lead to novel antibacterial compounds active against K. pneumoniae and other problematic Gram-negative pathogens. While there are many promising antibacterial targets in the periplasm, no convenient method exists to study the exact location of a compound in the Gram-negative cell, and there is no means to direct a compound to a specific subcellular localization. Using a novel imaging technology, the subcellular localization of scores of compounds will be tracked, and through this process the chemical traits that facilitate various subcellular localizations will be elucidated, with a special focus on the periplasm. This information will lead to a streamlined workflow for multi-parameter optimization of antibiotics and will be used to discover novel antibiotic candidates for important biological targets.

This grant is funded by The Wellcome Trust.

Andres Floto with Vitor Mendes, David Spring, Aaron Weimann, Sebastian Bruchmann, and José Miguel Hernández Lobato of the University of Cambridge in the United Kingdom will experimentally define the factors that control compound retention and xenometabolism in Klebsiella pneumoniae and the genetic determinants for variation in these processes across the phylogenetic diversity of this pathogen. The project will create predictive AI models of compound retention and stability by experimentally characterizing the chemical space of compounds that can accumulate inside this pathogen and remain stable. They will then use these models to steer chemical elaboration during structure-guided antibiotic discovery against novel targets, and make them freely available to academic and industry researchers.

This grant is funded by The Wellcome Trust.

Erick Strauss of Stellenbosch University in South Africa, in collaboration with co-investigators Andrew Whitelaw also of Stellenbosch University, Adrienne Edkins of Rhodes University in South Africa and Miquel Duran-Frigola of Ersilia Open Source Initiative in Spain will pursue the discovery of new Gram-negative antibacterials through the development of bacterial proteolysis targeting chimeras (BacPROTACs) - bifunctional molecules designed to engage high value protein targets and an endogenous intracellular protease in the pathogen to induce proteolytic degradation. In this manner, BacPROTACs use targeted protein degradation (TPD) as a highly innovative strategy to achieve an antibacterial outcome. The team proposes to use this approach to establish a BacPROTAC development workflow that can be applied for the identification of new chemical leads for any validated drug target or resistance-inducing factor that can be shown to be degraded by the pathogen’s endogenous protease, and for which a target-engaging ligand (TEL) can be identified.

This grant is funded by The Wellcome Trust.

Daniel Inaoka of the Institute of Tropical Medicine Nagasaki University and Yohei Doi of Fujita Health University, both in Japan, will aim to identify novel antibacterial compounds with new mechanisms of action (MoAs) against Klebsiella pneumoniae. By integrating high-throughput screening, transcriptomic profiling (Quartz-seq2), and genomic analysis, they will systematically discover and characterize compounds with distinct MoAs from existing antibiotics. Approximately 260,000 compounds from Japan’s two largest academic libraries will be screened. Active hits will be confirmed and validated, with transcriptomic clustering and machine learning applied to efficiently identify candidates with new MoAs. Resistant mutants will then be generated and analyzed by whole-genome sequencing to elucidate molecular targets.

This grant is funded by The Wellcome Trust.

Stephen Dela Ahator of the University of Ghana in Ghana, will pioneer a project involving multidisciplinary platform combining chemoproteomics and machine learning to accelerate the discovery of next-generation antimicrobials against Klebsiella. Using activity-based protein profiling, the project aims to map the functional landscape of bacterial bioactive enzymes to identify evolutionarily conserved and druggable targets. A hybrid graph neural network model will then predict and prioritize small-molecule inhibitors with high specificity and low human cross-reactivity. Lead compounds will be experimentally validated for potency, selectivity, and safety in infection models. By integrating functional proteomics with AI-driven compound screening, this project will aim to deliver new therapeutic scaffolds, establish an adaptable antimicrobial discovery pipeline, and strengthen research capacity through international collaboration between Ghana, Norway, the UK, and New Zealand.

This grant is funded by The Wellcome Trust.

Eachan Johnson of the Francis Crick Institute in the United Kingdom will develop a platform to accelerate the discovery of new antibiotics for Klebsiella pneumoniae, a major cause of drug-resistant infections worldwide. The project aims to understand which bacterial genes are most critical for survival across diverse conditions, and to use that knowledge to identify new ways to disable the bacterium during infection. They will build an integrated, scalable approach that combines genetic tools with phenotypic screening to reveal how chemical compounds act on Klebsiella pneumoniae and to highlight those with the greatest promise as starting points for new treatments. The work will generate foundational datasets, resources, and protocols to strengthen drug-discovery capacity across the Gr-ADI consortium, with the long-term goal of enabling more reliable, mechanism-guided development of antibiotics for Gram-negative infections.

Daniel Kahne of Harvard University, Thomas Bernhardt and Andrew Kruse of Harvard Medical School, and Jiankun Lyu of the Rockefeller University, all in the U.S. will discover novel antibiotics that target essential processes required for cell surface biogenesis in the Gram-negative pathogen Klebsiella pneumoniae. This bacterium and its relatives surround themselves with a multilayered cell surface composed of two membranes - an inner and an outer membrane - sandwiching a cell wall matrix made of the heteropolymer peptidoglycan. This surface architecture prevents many drugs from entering Gram-negative bacterial cells, giving them a high intrinsic resistance to antibiotics. Few therapeutic options are available for treating infections caused by these organisms, especially those that have acquired resistance to carbapenem antibiotics. This project will address the urgent clinical need for novel antibiotics effective against K. pneumoniae and other Gram-negative bacteria by identifying new inhibitors of outer membrane and peptidoglycan biogenesis.

Jason Peters of the University of Wisconsin in the U.S. will identify high-priority Klebsiella genes for targeting with mono- or poly-therapies using comprehensive, state-of-the-art functional genomics approaches.

Yves Brun of the University of Montréal and Mike Tyers of the Hospital for Sick Children in collaboration with colleagues at the Québec Institute for Learning Algorithms, the Institute for Research in Immunology and Cancer, SickKids, the University of Toronto and Simmunome Inc., all in Canada, will combine generative machine learning (ML) with high-throughput phenotypic- and target-based screens to identify new antibiotics against multidrug-resistant Klebsiella. The multidisciplinary team will use high-content microscopy and genome-wide CRISPRi to generate phenotypic and genetic profiles of Klebsiella responses to compounds and then train ML models on antibiotic activity, penetration, and resistance. In parallel, the team will use generative ML to design novel, synthesizable compounds against key Klebsiella targets, which will be produced by parallelized chemical synthesis and tested for antibiotic activity. A lab-in-the-loop active learning approach will be used to iteratively optimize ML models to predict potent new antibiotics active against Klebsiella.

Marisa Fabiana Nicolás of the National Laboratory for Scientific Computing in Brazil, alongside other research groups in Brazil and collaborators from Argentina, Chile, Mexico, Uruguay, Canada, and Portugal, will lead an interdisciplinary project to discover and validate small-molecule inhibitors targeting Klebsiella pneumoniae proteins. The team will integrate supercomputing, AI-driven modeling, CRISPRi knockdowns, Ribo-seq, enzymatic, and structural assays to identify high-value bacterial targets and generate validated small-molecule inhibitors. Target prioritization will be performed using the Target-Pathogen platform. Selected high-priority targets will be validated using CRISPRi strains, followed by virtual screening with DockThor-VS and rational design via DockTDesign to identify and optimize novel compounds. Hit compounds will be synthesized, tested in vitro, and evaluated through structure-activity relationship (SAR) analysis and on-target validation experiments to confirm antibacterial activity and target engagement. The ultimate goal is to deliver validated lead compounds with strong therapeutic potential against multidrug-resistant K. Pneumoniae.