baumannii is primarily associated with modifications to or complete loss of lipid A 18, 19, 20, 21, 22, 23. This process is accompanied by an increase in the production of reactive oxygen species (ROS) within the bacterial cell, which ultimately leads to cell death 17. This interaction between colistin and lipid A has been shown to induce membrane permeabilization and cell leakage 16. Colistin is a polycationic peptide that acts on Gram-negative bacteria by binding to the anionic lipid A component of the lipooligosaccharides (LOS) in the outer membrane, as well as the lipid A found in the inner membrane 14, 15. In addition to the constraints encountered in the clinical application of colistin, the emergence of multiple resistance mechanisms against this antibiotic further limits its efficacy during the treatment of recalcitrant infections. Moreover, colistin is less effective when applied in vivo, since its efficacy often does not match results obtained by in vitro studies, with up to 70% of patients failing to respond to colistin treatment 13. Indeed, only 50% of patients with normal renal function are able to maintain concentrations of colistin in their serum at levels that are sufficient to eliminate bacteria 11, 12. Despite needing to resort to treating patients with colistin, its efficacy in the clinic remains limited primarily due to strict dose restrictions. Nonetheless, the increased prevalence of MDR pathogens over the last three decades, and in particular the continuous emergence of resistance against complex β-lactam antibiotics like carbapenems, has forced clinicians to re-introduce colistin for the treatment of challenging infections 7, 8, 9, 10. baumannii infections severely diminished, clinical reliance on the last-resort antibiotic colistin for the treatment of recalcitrant infections has increased, resulting in a surge of colistin resistance in clinical strains 4, 5, 6.Ĭolistin was first introduced in the clinic in the 1950’s, however severe side effects, such as nephrotoxicity and neurotoxicity, led to its removal from therapeutic use in the 1970’s. For this reason, the World Health Organisation has classified this organism as a critical priority pathogen for which novel therapeutics are urgently needed 3. baumannii can reach as high as 70% in certain parts of the world 2. The prevalence of multidrug resistance among clinical isolates of A. 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.Īcinetobacter baumannii is a Gram-negative bacterium that causes pneumonia, as well as wound, bloodstream and urinary tract infections in hospital and community settings 1. coli in vitro and in the Galleria mellonella model of infection. Furthermore, we show that this vulnerability can be exploited to overcome both intrinsic and acquired colistin resistance in clinical strains of A.
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. 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. When administered singularly, kaempferol has no effect on growth but does impact biofilm formation. In this study, we identify the phytochemical kaempferol as a potentiator of colistin activity. However, the emergence of resistance against this last-line drug has significantly increased amongst clinical strains. baumannii largely relies on the use of colistin in cases where other treatment options have been exhausted.
Acinetobacter baumannii is a Gram-negative priority pathogen that can readily overcome antibiotic treatment through a range of intrinsic and acquired resistance mechanisms.
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