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Volume 169, Issue 12

Atomistic modelling and NMR studies reveal that gallium can target the ferric PQS uptake system in biofilms Open Access

Abstract

Intravenous gallium nitrate therapy is a novel therapeutic strategy deployed to combat chronic biofilm infections in the lungs of cystic fibrosis (CF) patients by interfering with iron (Fe) uptake. The therapy is a source of Ga, which competes with Fe for siderophore binding, subsequently disrupting iron metabolism and inhibiting biofilm proliferation . It was recently demonstrated that the quinolone signal (PQS) can chelate Fe to assist in bacterial iron uptake. However, it is unknown whether exogenous gallium also targets [Fe(PQS)] uptake, which, in turn, would extend the mechanism of gallium therapy beyond siderophore competition, potentially supporting use of the therapy against mutants deficient in siderophore uptake proteins. To that end, the thermodynamic feasibility of iron-for-gallium cation exchange into [Fe(PQS)] was evaluated using quantum chemical density functional theory (DFT) modelling and verified experimentally using H nuclear magnetic resonance (NMR). We demonstrate here that Ga can strongly bind to three PQS molecules and, furthermore, displace and substitute Fe from the native chelate pocket within PQS complexes, through a Trojan horse mechanism, retaining the key structural features present within the native ferric complex. As such, [Fe(PQS)] complexes, in addition to ferric–siderophore complexes, represent another target for gallium therapy.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): DFT , gallium , NMR and PQS
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2023-12-20
2024-05-15
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Atomistic modelling and NMR studies reveal that gallium can target the ferric PQS uptake system in P. aeruginosa biofilms
Microbiology 169, 001422 (2023); https://doi.org/10.1099/mic.0.001422
/content/journal/micro/10.1099/mic.0.001422
/content/journal/micro/10.1099/mic.0.001422
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