Urgent action is required to stem the apocalyptic spread of antimicrobial resistance (AMR). However, because the pace of novel drug development lags behind the evolution of novel AMR determinants, new strategies of containment are required.
Completed project
In this multinational proposal we develop a resistance-reversal strategy based on the concept of collateral sensitivity (CS). CS between a pair of antibiotics occurs when resistance to one antibiotic potentiates susceptibility to another. Thus, by exploiting CS relationships through sequential drug application, resistant strains can be specifically targeted which will reduce their frequencies in the community and arrest their transmission.
Our broad aim in this proposal is to realize the unique promise of CS-informed therapies. To do so, our work packages (WP) integrate theoretical biology, evolutionary and molecular microbiology, and in vivo modeling with a specific focus on arresting the transmission of resistant E. coli and S. pneumoniae.
The expected outcomes of the proposal are to provide pre-clinical recommendations for therapy to reduce the emergence and transmission of these two globally important bacterial pathogens and to provide a framework to develop CS-based strategies for other bacterial threats.
UiT, The Arctic University of Norway, coordinates the project and run two WPs in this JPI-EC-AMR project. One WP includes experimental work on E. coli where we test if general patterns of CS can be identified in clinical E. coli strains and how horizontal gene transfer affects these networks. The other WP aims to develop a modelling framework that furthers our understanding of sequential therapy within patients in the context of CS that is scalable to investigate transmission across patient populations.
Project partners
- Pål Jarle Johnsen, The Arctic University of Norway, Norway (Coordinator)
- Daniel Rozen, Leiden University, Netherlands
- Pia Abel zur Wiesch, The Arctic University of Norway, Norway
- Dan Andersson, Uppsala University, Sweden
- Niels Frimodt-Møller, Rigshospitalet, Denmark
Project resources
Presentation of the project by coordinator Pål Jarle Johnsen: Video COLLATERALDAMAGE, February 2022
Microbiology Research Group, The Arctic University of Norway, lead by project coordinator Pål Jarle Johnsen
Publications
- PloS Biology, 2020. Molecular mechanisms of collateral sensitivity to the antibiotic nitrofurantoin
- Scandinavian Journal of Primary Health Care, 2020. Retrospective study of men with E. coli UTI treated with an oral antibiotic, and risk for a new prescription or hospital admission due to UTI
- Nature Communications, 2018. Conserved collateral antibiotic susceptibility networks in diverse clinical strains of Escherichia coli
- PNAS, 2018. Cellular hysteresis as a principle to maximize the efficacy of antibiotic therapy
- Cell. Mol. Life Sci. 77, 2020. Multi-scale modeling of drug binding kinetics to predict drug efficacy.
- PLoS Comput Biol, 2020. Drug-target binding quantitatively predicts optimal antibiotic dose levels in quinolones.
- Nat Commun, 2019. Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase.
- FEMS Microbiology Reviews, 2020. Antibiotic resistance: turning evolutionary principles into clinical reality
- EClinicalMedicine, 2019. Three versus five days of pivmecillinam for community-acquired uncomplicated lower urinary tract infection: A randomised, double-blind, placebo-controlled superiority trial.
- Infect Drug Resist, 2019. Pivmecillinam compared to other antimicrobials for community-acquired urinary tract infections with Escherichia coli, ESBL-producing or not – a retrospective cohort study.
- Journal of Antimicrobial Chemotherapy, 2019. Treatment duration of pivmecillinam in men, non-pregnant and pregnant women for community-acquired urinary tract infections caused by Escherichia coli: a retrospective Danish cohort study
- Antibiotics, 2019. “Pivmecillinam for Uncomplicated Lower Urinary Tract Infections Caused by Staphylococcus saprophyticus—Cumulative Observational Data from Four Recent Clinical Studies”
- mSphere. 2019. OXA-48-Mediated Ceftazidime-Avibactam Resistance Is Associated with Evolutionary Trade-Offs.
- PLoS Pathog, 2021. Mechanisms and therapeutic potential of collateral sensitivity to antibiotics.
- Antimicrob Agents Chemother, 2020. Ciprofloxacin Pharmacokinetics/Pharmacodynamics against Susceptible and Low-Level Resistant Escherichia coli Isolates in an Experimental Ascending Urinary Tract Infection Model in Mice.
- J Glob Antimicrob Resist, 2020. Manganese complex [Mn(CO)3(tpa-κ3N)]Br increases antibiotic sensitivity in multidrug resistant Streptococcus pneumoniae.
