{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:25:50Z","timestamp":1792729550939,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1176180"],"award-info":[{"award-number":["APP1176180"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1194130"],"award-info":[{"award-number":["APP1194130"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP2009677"],"award-info":[{"award-number":["APP2009677"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["P2ZHP3_184024"],"award-info":[{"award-number":["P2ZHP3_184024"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["SNSF grant number P2ZHP3_191292"],"award-info":[{"award-number":["SNSF grant number P2ZHP3_191292"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["FT170100006"],"award-info":[{"award-number":["FT170100006"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>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 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 + 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.<\/jats:p>","DOI":"10.3390\/antibiotics11040449","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T15:31:21Z","timestamp":1648222281000},"page":"449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5085-7163","authenticated-orcid":false,"given":"David M. P.","family":"De Oliveira","sequence":"first","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Keller","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8038-1656","authenticated-orcid":false,"given":"Andrew J.","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6036-6889","authenticated-orcid":false,"given":"Cheryl-Lynn Y.","family":"Ong","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nichaela","family":"Harbison-Price","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim M.","family":"El-Deeb","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7465-2517","authenticated-orcid":false,"given":"Gen","family":"Li","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Keller","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Bohlmann","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Brouwer","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0882-7881","authenticated-orcid":false,"given":"Andrew G.","family":"Turner","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Cork","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2275-7659","authenticated-orcid":false,"given":"Thomas R.","family":"Jones","sequence":"additional","affiliation":[{"name":"School of Earth and Environmental Sciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Paterson","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alastair G.","family":"McEwan","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6141-5179","authenticated-orcid":false,"given":"Mark R.","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1596-4841","authenticated-orcid":false,"given":"Christopher A.","family":"McDevitt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6302-7524","authenticated-orcid":false,"given":"Mark von","family":"Itzstein","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Walker","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e00181-19","DOI":"10.1128\/CMR.00181-19","article-title":"Antimicrobial resistance in ESKAPE pathogens","volume":"33","author":"Forde","year":"2020","journal-title":"Clin. 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