lwlinwei, thanks again. This is the new PBT2 paper

Open AccessArticle

Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria

by

David M. P. De Oliveira

^1,†,

Bernhard Keller

^1,†,

Andrew J. Hayes

²,

Cheryl-Lynn Y. Ong

¹,

Nichaela Harbison-Price

¹,

Ibrahim M. El-Deeb

³,

Gen Li

¹,

Nadia Keller

¹,

Lisa Bohlmann

¹,

Stephan Brouwer

¹,

Andrew G. Turner

¹,

Amanda J. Cork

¹,

Thomas R. Jones

⁴,

David L. Paterson

⁵,

Alastair G. McEwan

¹,

Mark R. Davies

²,

Christopher A. McDevitt

^2,‡,

Mark von Itzstein

^3,‡ and

Mark J. Walker

^1,*,‡

¹

Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia

²

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia

³

Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia

⁴

School of Earth and Environmental Sciences, The University of Queensland, Brisbane, QLD 4072, Australia

⁵

Australian Infectious Diseases Research Centre, UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4006, Australia

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

Equal contribution as corresponding authors.

Academic Editor: Karl Hansford

Antibiotics 2022, 11(4), 449; https://doi.org/10.3390/antibiotics11040449

Received: 7 February 2022 / Revised: 16 March 2022 / Accepted: 22 March 2022 / Published: 25 March 2022

(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume)

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Abstract

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. View Full-Text

Keywords: antimicrobial resistance; polymyxins; PBT2; ionophores; Gram-positive bacteria

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