BATTALION – Battling Pandemic Multi-Drug Resistant E. coli Infections
Worldwide spread of specific bacterial lineages (high-risk clones) is a hallmark of all successful nosocomial pathogens. However, our current understanding of the evolution, selection and rapid dissemination of these lineages is limited and this prevents accurate prediction of future emerging lineages, improved diagnostics, and optimized targeted treatment strategies.
In this project, we focus on Escherichia coli, the most common cause of bloodstream infections in the developed world. E. coli is also the most common cause of urinary tract infections (UTI), which in turn are the most common bacterial infections in the world. Bacteraemia and UTI are caused by a subset of E. coli termed extra-intestinal pathogenic E. coli (ExPEC). The problem presented by the scale of ExPEC infections is exacerbated by the number of cases involving multi-drug resistant (MDR) strains, which has resulted in MDR E. coli being included in the WHO global priority pathogen list.
The main objective of the project is to elucidate the underlying mechanisms that contribute to the evolution, selection and spread of successful bacterial lineages, by going beyond current state-of-the-art approaches by characterizing at a whole population level the variation of the genome, transcriptome and virulome of major E. coli clones.
The project is led by Prof. Jukka Corander (University of Oslo) with MicroPop and the Norwegian National Advisory Unit on Detection of Antimicrobial Resistance as partners. The project is funded by the Trond Mohn Foundation National Research Programme on Antimicrobial Resistance and part of the AMR-Bridge project headed by UiT.
The MicroPop group is coordinating the "Collateral Damage" project, funded by the Joint Programming Initiative on AntiMicrobial Resistance (JPI-AMR).
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. In this multi-disciplinary proposal we develop a resistancereversal strategy based on the concept of collateral sensitivity (CS). CS between a pair of antibiotics occurs when a mutation causing resistance to one antibiotic potentiates susceptibility to another.
By exploiting CS relationships through sequential drug application, resistant strains can be specifically targeted which will reduce their frequencies in the community and slow their transmission. Our broad aim in this proposal is to realize the unique promise of CS-informed therapies. To do so, our work packages integrate theoretical biology, evolutionary and molecular microbiology, and in vivo modeling with a specific focus on arresting the transmission of resistant Escherichia coli and Streptococcus pneumoniae.
Combining theory and experiments, we will:
- test the generality of CS across hundreds of clinical strains of E. coli, and S. pneumoniae;
- quantify how horizontal transmission of antimicrobial resistance determinants modify CS-networks;
- identify the underlying molecular mechanisms of CS; and
- determine the conditions under which CS mediated reversals of resistance occur in vivo.
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.
Partners in this project are:
- Daniel E. Rozen: Institute of Biology, Leiden University, The Netherlands
- Pia Abel zur Wiesch: Faculty of Health Sciences, UiT - The Arctic University of Norway
- Dan I. Andersson: Uppsala Biomedicinska Centrum BMC, Uppsala University, Sweden
- Niels Frimodt-Møller: Department of Clinical Microbiology, Rigshospitalet, Denmark