Collateral Damage: Using collateral sensitivity to reverse the selection and transmission of antibiotic resistance
New strategies to contain the evolution and spread of antimicrobial resistance (AMR) are needed. In this multinational project proposal 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 increases susceptibility to another. By exploiting CS relationships through sequential drug application, resistant strains can be specifically targeted which will reduce their frequencies and arrest their transmission. In this project we have gained significant insights on the sign, generality, magnitude, and mechanisms of collateral effects following resistance development in the globally important bacterial pathogens Escherichia coli, Salmonella enterica and Streptococcus pneumoniae. The project has provided several suggestions for specific sequential treatment options, ready for pre-clinical validation, to limit the evolution and transmission of antibiotic resistance.
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Eindverslag
English summary below.
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. Here 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 increases 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. This proposal integrates theoretical biology, evolutionary and molecular microbiology, with the aim of providing pre-clinical recommendations to reduce the emergence and transmission of resistant Escherichia coli and Streptococcus pneumoniae and to provide a framework to develop CS-based strategies for other pathogens.