Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component.As such, the polymyxin class of antibiotics, which exert bactericidal activity against Gram-negative pathogens, are ineffective against Gram-positive bacteria.The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin resistance in Gram-negative bacteria, independent of the lipopolysaccharide modification pathways that confer polymyxin resistance.Here, in combination with zinc, PBT2 was shown to canals & nubiola cava break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), Staphylococcus aureus (including methicillin-resistant S.aureus), and vancomycin-resistant Enterococcus faecium.
Using the globally disseminated M1T1 GAS strain 5448 as a proof of principle model, colistin in the presence of PBT2 sofia barclay sexy + zinc was shown to be bactericidal in activity.Any resistance that did arise imposed a substantial fitness cost.PBT2 + zinc dysregulated GAS metal ion homeostasis, notably decreasing the cellular manganese content.Using a murine model of wound infection, PBT2 in combination with zinc and colistin proved an efficacious treatment against streptococcal skin infection.These findings provide a foundation from which to investigate the utility of PBT2 and next-generation polymyxin antibiotics for the treatment of Gram-positive bacterial infections.