Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/11/4/449 |
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| author | David M. P. De Oliveira Bernhard Keller Andrew J. Hayes Cheryl-Lynn Y. Ong Nichaela Harbison-Price Ibrahim M. El-Deeb Gen Li Nadia Keller Lisa Bohlmann Stephan Brouwer Andrew G. Turner Amanda J. Cork Thomas R. Jones David L. Paterson Alastair G. McEwan Mark R. Davies Christopher A. McDevitt Mark von Itzstein Mark J. Walker |
| author_facet | David M. P. De Oliveira Bernhard Keller Andrew J. Hayes Cheryl-Lynn Y. Ong Nichaela Harbison-Price Ibrahim M. El-Deeb Gen Li Nadia Keller Lisa Bohlmann Stephan Brouwer Andrew G. Turner Amanda J. Cork Thomas R. Jones David L. Paterson Alastair G. McEwan Mark R. Davies Christopher A. McDevitt Mark von Itzstein Mark J. Walker |
| author_sort | David M. P. De Oliveira |
| collection | DOAJ |
| description | 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 <i>Streptococcus pyogenes</i> (Group A <i>Streptococcus</i>; GAS), <i>Staphylococcus aureus</i> (including methicillin-resistant <i>S. aureus</i>), and vancomycin-resistant <i>Enterococcus faecium</i>. 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. |
| first_indexed | 2024-03-09T11:15:35Z |
| format | Article |
| id | doaj.art-1be6b9530c0b43719c05faf3da6a377f |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T11:15:35Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-1be6b9530c0b43719c05faf3da6a377f2023-12-01T00:32:00ZengMDPI AGAntibiotics2079-63822022-03-0111444910.3390/antibiotics11040449Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive BacteriaDavid M. P. De Oliveira0Bernhard Keller1Andrew J. Hayes2Cheryl-Lynn Y. Ong3Nichaela Harbison-Price4Ibrahim M. El-Deeb5Gen Li6Nadia Keller7Lisa Bohlmann8Stephan Brouwer9Andrew G. Turner10Amanda J. Cork11Thomas R. Jones12David L. Paterson13Alastair G. McEwan14Mark R. Davies15Christopher A. McDevitt16Mark von Itzstein17Mark J. Walker18Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaDepartment of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaInstitute for Glycomics, Griffith University, Gold Coast, QLD 4222, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaSchool of Earth and Environmental Sciences, The University of Queensland, Brisbane, QLD 4072, AustraliaAustralian Infectious Diseases Research Centre, UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4006, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaDepartment of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, AustraliaDepartment of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, AustraliaInstitute for Glycomics, Griffith University, Gold Coast, QLD 4222, AustraliaAustralian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, AustraliaGram-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 <i>Streptococcus pyogenes</i> (Group A <i>Streptococcus</i>; GAS), <i>Staphylococcus aureus</i> (including methicillin-resistant <i>S. aureus</i>), and vancomycin-resistant <i>Enterococcus faecium</i>. 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.https://www.mdpi.com/2079-6382/11/4/449antimicrobial resistancepolymyxinsPBT2ionophoresGram-positive bacteria |
| spellingShingle | David M. P. De Oliveira Bernhard Keller Andrew J. Hayes Cheryl-Lynn Y. Ong Nichaela Harbison-Price Ibrahim M. El-Deeb Gen Li Nadia Keller Lisa Bohlmann Stephan Brouwer Andrew G. Turner Amanda J. Cork Thomas R. Jones David L. Paterson Alastair G. McEwan Mark R. Davies Christopher A. McDevitt Mark von Itzstein Mark J. Walker Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria Antibiotics antimicrobial resistance polymyxins PBT2 ionophores Gram-positive bacteria |
| title | Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria |
| title_full | Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria |
| title_fullStr | Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria |
| title_full_unstemmed | Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria |
| title_short | Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria |
| title_sort | neurodegenerative disease treatment drug pbt2 breaks intrinsic polymyxin resistance in gram positive bacteria |
| topic | antimicrobial resistance polymyxins PBT2 ionophores Gram-positive bacteria |
| url | https://www.mdpi.com/2079-6382/11/4/449 |
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