Control of bacterial infections is threatened by the rapid emergence of drug resistance, drug tolerance that mitigates antimicrobial efficacy, and the lack of new antibiotics in recent years. Combination treatments and/or re-purposing of known drugs can provide a cost- and time-efficient solution.
We propose a comprehensive and powerful strategy to repurpose or improve FDA-approved drugs including neglected/disused (ND) antibiotics, and identify combinations to re-sensitize resistant/tolerant bacteria. Using high-throughput screening (HTS), we will test thousands of pairwise drug combinations on bacterial growth, viability and bacterial persistence in three clinically relevant pathogens: uropathogenic Escherichia coli (UPEC), Staphylococcus aureus (Sa), and Streptococcus pneumoniae (Sp). Our scope thus spans the Gram-negative/-positive divide, and targets several bacterial states implicated in both acute and chronic infections, including pneumonia, pyelonephritis, bacteremia and endocarditis.
To optimize antimicrobial treatment, we will use state-of-the-art and further advance translational pharmacokinetic (PK)/ pharmacodynamic (PD) modeling. This will prioritize and validate lead combinations, which will be tested in several toxicity and animal models. In vivo PK/PD modeling will be also performed for our top leading combinations. Together, these approaches will provide invaluable pre-clinical data that will inform future drug development. In parallel, we will systematically probe for modes of action of our top 100 synergistic drug combinations using HT reverse genetic screens to provide the framework for subsequent in-depth mechanistic studies targeting processes such as the role of redox and iron homeostasis, membrane permeability/stability, drug efflux/influx and bacterial metabolism and stress responses in antimicrobial activity.
We have assembled a strong team with extensive expertise in the cellular processes directly related to antimicrobial activity. For this project, we will combine HT chemical and genetic screening, large-scale data analysis, mechanistic biology, PK/PD modelling and infection models to discover and exploit antimicrobial combination therapy. The breadth and scope of our ambitious strategy will undoubtedly significantly advance the quest for novel treatment strategies against bacterial infections.
- Typas Athanasios, European Molecular Biology Laboratory, Germany (Coordinator)
- Jan-Willem Veening, University of Groningen, Netherlands
- Frédéric Barras, CNRS, Aix‐Marseille Université, France
- Birgitta Henriques Normark, Karolinska Institutet, Sweden
- Charlotte Kloft, Freie Universität Berlin, Germany
- Bernt Eric Uhlin, Umeå University, Sweden
- Antibiotics, 2020. Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients—A Controlled Clinical Trial
- bioRxiv, 2020. Dissecting the collateral damage of antibiotics on gut microbes
- Cell Host & Microbe, 2020. Proton Motive Force Disruptors Block Bacterial Competence and Horizontal Gene Transfer
- Clinical Pharmacology & Therapeutics, 2020. Perspectives on Model‐Informed Precision Dosing in the Digital Health Era: Challenges, Opportunities, and Recommendations
- PLOS Genetics, 2020. Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis
- Genes, 2019. Three new integration vectors and fluorescent proteins for use in the opportunistic human pathogen Streptococcus pneumoniae
- Nature Microbiology, 2019. RocS drives chromosome segregation and nucleoid protection in Streptococcus pneumoniae
- bioRxiv, 2018. RocS drives chromosome segregation and nucleoid occlusion in Streptococcus pneumoniae
- Cell Reports, 2018. Antibiotic-induced cell chaining triggers pneumococcal competence by reshaping quorum sensing to autocrine signaling
- Nucleic Acid Research, 2018. Deep genome annotation of the opportunistic human pathogen Streptococcus pneumoniae D39
- Nature, 2018. Species-specific activity of antibacterial drug combinations
- Nucleic Acids Research, 2018. High-resolution analysis of the pneumococcal transcriptome under a wide range of infection-relevant conditions
- CPT: Pharmacometrics & Systemics Pharmacology, 2017. Translational Pharmacometric Evaluation of Typical Antibiotic Broad‐Spectrum Combination Therapies Against Staphylococcus Aureus Exploiting In Vitro Information
- Molecular Microbiology, 2017. Silver potentiates aminoglycoside toxicity by enhancing their uptake