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JPIAMR-JPI Antimikrobiell resistens

Using collateral sensitivity to reverse the selection and transmission of antibiotic resistance

Awarded: NOK 6.8 mill.

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 multinational project, co-ordinated from UiT- The Arctic University of Norway,l we have worked on 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. In this project we have gained significant insights on the sign, generality, magnitude, and mechanistics of collateral effects following resistance development in the globally important bacterial pathogens E. coli, Salmonella enterica and Streptococcus pneumoniae. The project has also provided several suggestions for specific sequential treatment options, ready for pre-clinical validation, to limit the evolution and transmission of antibiotic resistance. A potentially important spin off is the finding that the cytotoxic drug methotrexate display collateral-resistance to the antibiotic trimethoprim. Consequently, methotrexate has the potential to select and co-select for trimethoprim resistance and any linked genetic determinant, respectively.

Prosjektet COLLATERALDAMAGE har hatt følgende virkninger: 1. Vi har bidratt sterkt til økt forståelse av hvordan kollaterale nettverk i bakterier påvirker evolusjon og spredning av antibiotikaresistens. 2. Prosjektet har bidratt til å belyse flere underliggende mekanismer for kollateral effekter i bakterier 3. Prosjektet har bidratt til flere prekliniske anbefalinger for optimal bruk av antibiotika som kan potensielt redusere forekomst og spredning av resistens.

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 resistance- reversal 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: 1) test the generality of CS across hundreds of clinical strains of E. coli, and S. pneumoniae; 2) quantify how horizontal transmission of antimicrobial resistance determinants modify CS-networks; 3) identify the underlying molecular mechanisms of CS; and 4) 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.

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JPIAMR-JPI Antimikrobiell resistens