Novel drugs and drug combination against bacterial growth, survival and persistance; form high-throughput screening to mechanism of action
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 (Partner)
- Frédéric Barras, CNRS, Aix‐Marseille Université, France (Partner)
- Birgitta Henriques Normark, Karolinska Institutet, Sweden (Partner)
- Charlotte Kloft, Freie Universität Berlin, Germany (Partner)
- Bernt Eric Uhlin, Umeå University, Sweden (Partner)
Control of bacterial infections is threatened by the rapid emergence of drug resistance and the lack of new antibiotics in recent years. The effort required for developing new drugs and the limited profit margins for antibiotics has led most pharmaceuticals to close down their antibiotic R&D departments in the last 25 years. With infections by multi-drug-resistant (MDR) microbes rising alarmingly in clinics at the same timeframe, the stakes for reverting the situation urgently have become high. However, developing new effective drugs takes time, and is a process with a high attrition rate. Combination treatments and/or re-purposing of known drugs can provide a cost- and time-efficient solution, and address the urgent need for new therapies against life-threatening infections. As part of this consortium, we identified: a) antibiotic pairs that together have much higher activity than alone and allowed to target MDR pathogens; b) non-antibiotic compounds that potentiate the activity of poorly acting/neglected antibiotics and allow them to be active against MDR pathogens; c) non-antibiotic drugs with hidden antibacterial and adjuvant activities; d) non-antibiotic drugs that that can be used in combination with antibiotics to block antibiotic resistance development by impeding the ability of pathogens to take up DNA; and e) non-antibiotic drugs that reduce the collateral damage of antibiotics on our commensal microbiome.
- Cell Reports, 2018. Antibiotic-induced cell chaining triggers pneumococcal competence by reshaping quorum sensing to autocrine signaling
- Genes, 2019. Three new integration vectors and fluorescent proteins for use in the opportunistic human pathogen Streptococcus pneumoniae
- CPT: Pharmacometrics & Systemics Pharmacology, 2017. Translational Pharmacometric Evaluation of Typical Antibiotic Broad‐Spectrum Combination Therapies Against Staphylococcus Aureus Exploiting In Vitro Information
- Cell Host & Microbe, 2020. Proton Motive Force Disruptors Block Bacterial Competence and Horizontal Gene Transfer
- Nature Microbiology, 2019. RocS drives chromosome segregation and nucleoid protection in Streptococcus pneumoniae
- PLOS Genetics, 2020. Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis
- Antibiotics, 2020. Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients—A Controlled Clinical Trial
- Clinical Pharmacology & Therapeutics, 2020. Perspectives on Model‐Informed Precision Dosing in the Digital Health Era: Challenges, Opportunities, and Recommendations
- J Bacteriol, 2016. Antibodies Damage the Resilience of Fimbriae, Causing Them To Be Stiff and Tangled.
- Curr Opin Syst Biol, 2017. Chemical genetics in drug discovery.
- Nature, 2018. Species-specific activity of antibacterial drug combinations.
- Front Microbiol, 2018. Enhanced Biofilm Formation and Membrane Vesicle Release by Escherichia coli Expressing a Commonly Occurring Plasmid Gene, kil
- Diagnostics (Basel), 2020. Guideline for Urine Culture and Biochemical Identification of Bacterial Urinary Pathogens in Low-Resource Settings.
- Molecular Microbiology, 2017. Silver potentiates aminoglycoside toxicity by enhancing their uptake
- Nature, 2018. Species-specific activity of antibacterial drug combinations
- Nucleic Acid Research, 2018. Deep genome annotation of the opportunistic human pathogen Streptococcus pneumoniae D39
- Nucleic Acids Research, 2018. High-resolution analysis of the pneumococcal transcriptome under a wide range of infection-relevant conditions