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Small Molecule Potentiation of Gram-Positive Selective Antibiotics against Acinetobacter baumannii
journal contribution
posted on 2019-04-19, 00:00 authored by Sara E. Martin, Roberta J. Melander, Christopher M. Brackett, Alison J. Scott, Courtney E. Chandler, Catherine M. Nguyen, Bradley M. Minrovic, Sarah E. Harrill, Robert K. Ernst, Colin Manoil, Christian MelanderIn 2016, the World
Health Organization deemed antibiotic resistance one of the biggest
threats to global health, food security, and development. The need
for new methods to combat infections caused by antibiotic resistant
pathogens will require a variety of approaches to identifying effective
new therapeutic strategies. One approach is the identification of
small molecule adjuvants that potentiate the activity of antibiotics
of demonstrated utility, whose efficacy is abated by resistance, both
acquired and intrinsic. To this end, we have identified compounds
that enhance the efficacy of antibiotics normally ineffective against
Gram-negative pathogens because of the outer membrane permeability
barrier. We identified two adjuvant compounds that dramatically enhance
sensitivity of Acinetobacter baumannii to macrolide
and glycopeptide antibiotics, with reductions in minimum inhibitory
concentrations as high as 256-fold, and we observed activity across
a variety of clinical isolates. Mode of action studies indicate that these adjuvants likely work
by modulating lipopolysaccharide synthesis or assembly. The adjuvants
were active in vivo in a Galleria mellonella infection model, indicating potential for use in mammalian infections.