Disrupting iron homeostasis can potentiate colistin activity and overcome colistin resistance mechanisms in Gram-Negative Bacteria.
Resource type
Journal article
Date published
September 13, 2023
Abstract
is a Gram-negative priority pathogen that can readily overcome antibiotic treatment through a range of intrinsic and acquired resistance mechanisms. Treatment of carbapenem-resistant largely relies on the use of colistin in cases where other treatment options have been exhausted. However, the emergence of resistance against this last-line drug has significantly increased amongst clinical strains. In this study, we identify the phytochemical kaempferol as a potentiator of colistin activity. When administered singularly, kaempferol has no effect on growth but does impact biofilm formation. Nonetheless, co-administration of kaempferol with sub-inhibitory concentrations of colistin exposes bacteria to a metabolic Achilles heel, whereby kaempferol-induced dysregulation of iron homeostasis leads to bacterial killing. We demonstrate that this effect is due to the disruption of Fenton’s reaction, and therefore to a lethal build-up of toxic reactive oxygen species in the cell. Furthermore, we show that this vulnerability can be exploited to overcome both intrinsic and acquired colistin resistance in clinical strains of and in vitro and in the model of infection. Overall, our findings provide a proof-of-principle demonstration that targeting iron homeostasis is a promising strategy for enhancing the efficacy of colistin and overcoming colistin-resistant infections.
Project(s)
Priority 2: Trait Diversity and Function
Funder
| Funder name | Awards |
RCUK | Biotechnology and Biological Sciences Research Council | BB/V007823/1 |
Academy of Medical Sciences | SBF006\1040 |
U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases | R01AI158753 |
Journal title
Communications Biology
Volume
6
Article number
937
Publisher
Springer Science and Business Media LLC
Place of publication
Berlin/Heidelberg, Germany
eISSN
2399-3642
Date accepted
August 29, 2023
Official URL
Rights statement
In Copyright