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...
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MDPI AG,
2022-03-01T00:00:00Z.
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|---|---|---|---|
| 001 | doaj_1be6b9530c0b43719c05faf3da6a377f | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a David M. P. De Oliveira |e author |
| 700 | 1 | 0 | |a Bernhard Keller |e author |
| 700 | 1 | 0 | |a Andrew J. Hayes |e author |
| 700 | 1 | 0 | |a Cheryl-Lynn Y. Ong |e author |
| 700 | 1 | 0 | |a Nichaela Harbison-Price |e author |
| 700 | 1 | 0 | |a Ibrahim M. El-Deeb |e author |
| 700 | 1 | 0 | |a Gen Li |e author |
| 700 | 1 | 0 | |a Nadia Keller |e author |
| 700 | 1 | 0 | |a Lisa Bohlmann |e author |
| 700 | 1 | 0 | |a Stephan Brouwer |e author |
| 700 | 1 | 0 | |a Andrew G. Turner |e author |
| 700 | 1 | 0 | |a Amanda J. Cork |e author |
| 700 | 1 | 0 | |a Thomas R. Jones |e author |
| 700 | 1 | 0 | |a David L. Paterson |e author |
| 700 | 1 | 0 | |a Alastair G. McEwan |e author |
| 700 | 1 | 0 | |a Mark R. Davies |e author |
| 700 | 1 | 0 | |a Christopher A. McDevitt |e author |
| 700 | 1 | 0 | |a Mark von Itzstein |e author |
| 700 | 1 | 0 | |a Mark J. Walker |e author |
| 245 | 0 | 0 | |a Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria |
| 260 | |b MDPI AG, |c 2022-03-01T00:00:00Z. | ||
| 500 | |a 10.3390/antibiotics11040449 | ||
| 500 | |a 2079-6382 | ||
| 520 | |a 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. | ||
| 546 | |a EN | ||
| 690 | |a antimicrobial resistance | ||
| 690 | |a polymyxins | ||
| 690 | |a PBT2 | ||
| 690 | |a ionophores | ||
| 690 | |a Gram-positive bacteria | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Antibiotics, Vol 11, Iss 4, p 449 (2022) | |
| 787 | 0 | |n https://www.mdpi.com/2079-6382/11/4/449 | |
| 787 | 0 | |n https://doaj.org/toc/2079-6382 | |
| 856 | 4 | 1 | |u https://doaj.org/article/1be6b9530c0b43719c05faf3da6a377f |z Connect to this object online. |