Carbohydrate cOnjugates as Trojan horsE to improve Antibiotic iMport – CO-TEAM

The increase of antimicrobial resistance is a major threat for individual and public health. Consequently, new weapons to fight the emerging multidrug-resistant bacteria are quickly required. The ESKAPE pathogens are at the frontline of these problematic life-threatening drug resistant nosocomial pathogens. In this project, we aim to overcome antimicrobial resistance by hijacking energy-driven carbohydrate uptake systems (PTS and ABC transporters) to actively pump carbohydrate-antibiotic conjugates into bacteria which will be liberated by cellular glycosidases. These transporters are able to accumulate mM intracellular concentrations of their substrates. Exploring if they will boost intracellular concentrations of the carbohydrate-antibiotic conjugates as well is the main objective of the CO-TEAM project. Our preliminary work shows that the expression of the transporters of these carbohydrates is significantly induced under infection conditions. The project is divided into 4 tasks. 4 different oligosaccharide conjugates carrying 6 different antibiotics from 4 different classes will be chemically synthesized. These conjugates will then be studied for antimicrobial efficacy and resistance development against a panel of strains with a focus on the most urgent ESKAPE pathogens. In addition, mechanistic analyses to identify the transporters importing the conjugates will be conducted in 2 Gram-positive and 2 Gram-negative pathogens. Finally, we will evaluate the most promising conjugates in an insect and mouse model. Boosting intracellular antibiotic concentrations through active import is expected to overcome antimicrobial resistance mechanisms, both, target modifications lowering the antibiotic's efficacy, also permeability affecting resistance, the major problem in Gram-negative bacteria.