De Oliveira, D.M.P.Keller, B.Hayes, A.J.Ong, C.-L.Y.Harbison-Price, N.El-Deeb, I.M.Li, G.Keller, N.Bohlmann, L.Brouwer, S.Turner, A.G.Cork, A.J.Jones, T.R.Paterson, D.L.McEwan, A.G.Davies, M.R.McDevitt, C.A.Itzstein, M.V.Walker, M.J.2022-05-162022-05-162022Antibiotics, 2022; 11(4):449-1-449-152079-63822079-6382https://hdl.handle.net/2440/135123Gram-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 break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), Staphylococcus aureus (including methicillinresistant 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 + 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.en© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).antimicrobial resistancepolymyxinsPBT2ionophoresGram-positive bacteriaJournal article10.3390/antibiotics110404492022-05-16609228McDevitt, C.A. [0000-0003-1596-4841]