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.

Everett Tate of the University of Chicago in the U.S., with collaborators in the United Arab Emirates, Ghana, Kenya, South Africa, and India, will establish a multi-site consortium for research on heavy menstrual bleeding. Consortium sites, including hospitals, clinics, and universities, will standardize processes for collecting patient samples and data, and they will establish a database integrating immune and cytokine profiling, genetic analysis, and ultrasound imaging, including AI-based data modeling. They will also perform epidemiological analyses, incorporating data gathered from patients visiting mobile health vans, to better understand the geospatial distribution of heavy menstrual bleeding prevalence and risk. The consortium approach will provide a framework to improve the accuracy, efficiency, and accessibility of early diagnosis of the condition in low-resource settings.

Ayokunle Olanrewaju, and collaborators Ashleigh Theberge and Erwin Berthier, of the University of Washington in the U.S. will develop a platform for at-home self-collection of blood, serum separation, and sample stabilization at sufficient sample volumes for comprehensive HIV monitoring. An existing device for home blood collection will be expanded with the development of serum separation using a simple filtration system and connected to a standard blood collection tube with serum-stabilizing reagents. The device design will be optimized to ensure that over 1 mL of blood can be processed. The resulting design will then be tested for its effectiveness for RNA and protein analysis to monitor HIV viral load and biomarkers associated with HIV treatment and care. Performance of the device will be compared to standard blood processing, using blood from healthy volunteers spiked with either HIV RNA or C-reactive protein as a model biomarker. They envision a system that can readily integrate with standard laboratory or point-of-care diagnostic workflows to enable maximal deployability.

Hatice Ceylan Koydemir with Sandun Fernando at Texas A&M University in the U.S., working with Levent Beker and Ebru Celik of Koç University in Turkey, will develop an affordable point-of-care diagnostic platform for prediction and detection of preeclampsia early in pregnancy. By employing sensor miniaturization and integrating with low-cost electronic devices, they aim to provide a battery-less, easy-to-use, portable platform for automated data analysis at the point of care, particularly suitable for use in low- and middle-income countries (LMICs). They will evaluate the prototype device using human serum samples spiked with preeclampsia biomarker proteins, as well as serum samples collected from over 100 participants at Koç University Hospital in Turkey and an LMIC setting, comparing the device's results to hospital clinical reports.

Lisa Rohan of the University of Pittsburgh in the U.S., with Thesla Palanee-Phillips of the Wits Health Consortium (Pty) Ltd in South Africa, will develop a vaginal film technology for the sustained release of the hormone levonorgestrel as a product that provides contraception and reduces heavy menstrual bleeding. Levonorgestrel is a progestin, a synthetic hormone that mimics the effects of progesterone. They will create and compare vaginal films with differences in mechanical properties, mucoadhesion, and drug release profiles to design a product that is low-cost, self-administered, and active for one month. They will also conduct a pilot trial of two prototype placebo films without levonorgestrel, evaluating them for safety, acceptability, and mucoadhesion in 20 women in South Africa, half with heavy menstrual bleeding.

Joyce Were of the Kenya Medical Research Institute in Kenya will develop a screening tool for assessing heavy menstrual bleeding that is adapted for use in Kenya by integrating two globally used questionnaires, adding material to incorporate the impact on women in the Kenyan context, and translating it into the locally spoken languages Swahili and Luo. Through consultations with experts, the tool will combine the Menstrual Bleeding Questionnaire (MBQ) with the Screening Assessment and Measurement of Atypical and Normal Menstrual Patterns Tool for Adolescents and Adults (SAMANTA), and it will incorporate new questions. The tool will be iteratively modified through small pilot tests. It will then be administered to adolescent girls and young women in Western Kenya as part of the Health and Demographic Surveillance System (HDSS) of the Kenya Medical Research Institute (KEMRI), with 70,000 participants surveyed with either the new tool or the MBQ or SAMANTA tools for comparison.

Jennifer Anyanti of the Society for Family Health with Clara Ejembi from Ahmadu Bello University, both in Nigeria, will evaluate patient experiences and treatment outcomes in women with heavy menstrual bleeding in Nigeria, with a focus on increasing the effectiveness, acceptability, and accessibility of hormonal contraceptives as treatment. Clinical data will be collected for a cohort of women receiving care for the condition in Kaduna state in Nigeria, together with qualitative data from interviews with patients, care providers, and supply chain managers. This information will be used to design and pilot targeted interventions to increase access to acceptable and effective treatment, such as community health education, supply chain improvements, and treatment programs. Such interventions can be iteratively improved with the original evaluation framework, generating a sustainable data management system to guide improvements in patient-centered care for heavy menstrual bleeding.

Anne Beatrice Kihara with Moses Madadi, both of the University of Nairobi in Kenya, will pilot a multipronged approach to support research and development for women’s health in Kenya. They will co-develop a policy and regulatory framework that integrates gender equity, working with government stakeholders, including the Ministry of Health and regulators, as well as civil society groups and women-led organizations. They will develop case studies of healthcare technologies for women’s health, focused on how accessible these technologies are for women in underserved communities; launch community-based campaigns to increase awareness and understanding of women’s health and healthcare solutions; and train healthcare professionals in applying an equity perspective in women’s health research and care. Community feedback will guide an iterative approach throughout these efforts.