Thiocillin and micrococcin exploit the ferrioxamine receptor of Pseudomonas aeruginosa for uptake Academic Article uri icon

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abstract

  • Abstract Background 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. Objectives To test other thiopeptides for antimicrobial activity against P. aeruginosa and determine their mechanism of uptake, action and spectrum of activity. Methods 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. Results 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. Conclusions 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.

publication date

  • July 15, 2021