All Awards

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.

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.

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.