Overcoming drug resistance with alginate oligosaccharides able to 1 potentiate the action of selected antibiotics 2 3 4

29 The uncontrolled, often inappropriate use of antibiotics has resulted in the increasing 30 prevalence of antibiotic-resistant pathogens, with major cost implications for both US and 31 European healthcare systems. We describe the utilization of a low molecular weight 32 oligosaccharide nanomedicine (OligoG) based on the biopolymer alginate, which is able to 33 perturb multi-drug resistant (MDR) bacteria by modulating biofilm formation/persistence 34 and reducing resistance to antibiotic treatment; evident using conventional and robotic MIC 35 screening and microscopic analyses of biofilm structure. OligoG increased the efficacy of 36 conventional antibiotics (up to 512-fold) against important MDR pathogens including 37 Pseudomonas, Acinetobacter and Burkholderia spp., appearing to be effective with several 38 classes of antibiotic (i.e. macrolides, β-lactams, tetracyclines). Using confocal laser 39 scanning microscopy (CLSM) and scanning electron microscopy (SEM) increasing 40 concentrations of alginate oligomer (2, 6 and 10%) were shown have a direct effect on the 41 quality of the biofilms produced and on the health of the cells within that biofilm. Biofilm 42 growth was visibly weakened in the presence of 10% OligoG as seen by decreased biomass 43 and increased intercellular spaces, with the bacterial cells themselves becoming distorted and 44 uneven due to apparently damaged cell membranes. This study demonstrates the feasibility 45 of reducing the tolerance of wound biofilms to antibiotics with the use of specific alginate 46