NCCR AntiResist: New approaches to combat antibiotic-resistant bacteria

The overarching goal of this project is to elucidate the physiological properties of bacterial pathogens in infected human patients in order to provide new ways of combatting superbugs. Over the past decades, pan-resistant strains of major bacterial pathogens have emerged that have rendered clinically available antibiotics ineffective, putting at risk many of the major achievements of modern medicine, including surgery, cancer therapy and organ transplantation. New antibacterial agents and alternative strategies to identify clinically useful antimicrobials are, thus, urgently needed. The current development pipeline of new antimicrobials is insufficient to meet the anticipated need, in particular because the attrition rate is inherently high and only a minority of the drug candidates addresses Gram-negative bacteria. Among the many societal, economic, and scientific factors that impact on the development of alternative strategies for antibiotic identification, our limited understanding of the physiology and heterogeneity of bacterial pathogens in patients ranks highly. Bacteria growing in tissues of patients experience environments very different from standard laboratory conditions, resulting in radical differences in microbial physiology and population heterogeneity between the target population and that used for antibacterial discovery. There is currently no systematic strategy to deal with this fundamental problem. This has resulted in: (i) suboptimal screens that identify new antibiotics, which do not target the special properties of bacteria growing within the patient; (ii) an inability to properly evaluate the efficacy of non-conventional antibacterial strategies; (iii) missed opportunities for entirely new treatment strategies.This NCCR will utilize patient samples from ongoing clinical studies and establish a unique multidisciplinary network of clinicians, biologists, engineers, chemists, computational scientists and drug developers that will overcome this problem. We are excited to bring these disciplines together to determine the properties of pathogens infecting patients, establish conditions in the lab that reproduce these properties and utilize these in-vitro models for antimicrobial discovery and development. Switzerland has world-renowned scientists in areas ranging from single-cell analysis to microbial behavior in tissue sites. In addition, clinical-trial networks and the pharmaceutical industry have major footprints in antimicrobial R&D. Exploiting synergies between these players has great potential for making transformative progress in this critical field of human health. Our team has already established many links through programs such as: SystemsX.ch; NRP72; IMI-ND4BB; SPHN/PHRT; Gerbert Rüf Foundation; Biolink; Marie Curie ITNs. We also have active industry collaborations with Biotech SMEs and large pharmaceutical companies. We will extend these collaborations, include additional partners and promote long-term bridging of disparate disciplines with a new graduate teaching program to train the next generation of scientists in interdisciplinary approaches. Through these efforts, we will:•accelerate antibiotic discovery by providing relevant read-outs for early prioritization of compounds;•enable innovative screens for non-canonical strategies such as anti-virulence inhibitors and immunomodulators;•identify entirely new antibacterial strategies that effectively combat bacteria either by targeting refractory subpopulations or by synergizing with bacterial stresses imposed by the patients’ own immune system.The NCCR will progress from clinical and basic research to technology and development in three four-year phases: Phase 1: From conditions in patients to laboratory models. We will focus on infections by four critical bacterial pathogens. We will use freshly frozen patient samples to: (i) determine conditions that pathogens face in infected tissues using metabolomics and proteomics; (ii) quantify single-cell and bulk average pathogen properties using novel chemical tools as well as transcriptomics and proteomics. We use these data to guide and benchmark development of patient-mimicking, in-vitro models ranging from axenic conditions to 3D-micro-tissues. We will utilize the best systems to accelerate the search for novel bacterial targets, antibacterial compounds and non-conventional strategies, in part through expanding collaborations with the pharmaceutical companies Roche, Polyphor, and BioVersys.Phase 2: From laboratory models to screening platforms. We will use validated patient-like models from Phase 1 to build high-throughput screening platforms. We will use these assays for target identification and validation, antibacterial discovery and development of non-conventional strategies in collaboration with industrial partners. We will build a second generation of models with more accurate representation of interactions between the innate immune system and pathogens. We will include additional important pathogens. Phase 3: Implementation in drug discovery, development pipelines and clinics. The most promising targets, assays and predictive features will be used to expand the drug-discovery pipeline and to develop novel therapies, again in close collaboration with industry and hospitals.This NCCR proposes a paradigm shift in antibiotic discovery: we will investigate the physiology of bacterial pathogens in human patient. We will use this knowledge to develop assays for molecular analyses and drug screening under relevant conditions. These assays will accelerate antibacterial discovery, improve treatment regimens, and uncover novel targets for eradicating pathogens. This concerted effort will make a crucial and unique contribution to winning the race against superbugs.