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Thiocillin and micrococcin exploit the ferrioxamine receptor of Pseudomonas aeruginosa for uptake.

Authors
  • Chan, Derek C K1, 2
  • Burrows, Lori L1, 2
  • 1 Department of Biochemistry and Biomedical Sciences, McMaster Children's Hospital, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada. , (Canada)
  • 2 Michael G. DeGroote Institute for Infectious Diseases Research, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada. , (Canada)
Type
Published Article
Journal
Journal of Antimicrobial Chemotherapy
Publisher
Oxford University Press
Publication Date
Jul 15, 2021
Volume
76
Issue
8
Pages
2029–2039
Identifiers
DOI: 10.1093/jac/dkab124
PMID: 33907816
Source
Medline
Language
English
License
Unknown

Abstract

Thiopeptides are a class of antibiotics that are active against Gram-positive bacteria and inhibit translation. They were considered inactive against Gram-negative bacteria due to their inability to cross the outer membrane. However, we discovered previously that a member of this class, thiostrepton (TS), has activity against Pseudomonas aeruginosa and Acinetobacter baumannii under iron-limiting conditions. TS hijacks the pyoverdine siderophore receptors of P. aeruginosa to cross the outer membrane and synergizes with iron chelators. To test other thiopeptides for antimicrobial activity against P. aeruginosa and determine their mechanism of uptake, action and spectrum of activity. Eight thiopeptides were screened in chequerboard assays against a mutant of P. aeruginosa PA14 lacking both pyoverdine receptors. Thiopeptides that retain activity against a pyoverdine receptor-null mutant may use alternative siderophore receptors for entry. Susceptibility testing against siderophore receptor mutants was used to determine thiopeptide mechanism of uptake. The thiopeptides thiocillin (TC) and micrococcin (MC) use the ferrioxamine siderophore receptor (FoxA) for uptake and inhibit the growth of P. aeruginosa at low micromolar concentrations. The activity of TC required the TonB-ExbBD system used to energize siderophore uptake. TC acted through its canonical mechanism of action of translation inhibition. Multiple thiopeptides have antimicrobial activity against P. aeruginosa, countering the historical assumption that they cannot cross the outer membrane. These results demonstrate the potential for thiopeptides to act as antipseudomonal antibiotics. © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected]

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