Disrupting iron homeostasis can potentiate colistin activity and overcome colistin resistance mechanisms in Gram-Negative Bacteria.
Disrupting iron homeostasis can potentiate colistin activity and overcome colistin resistance mechanisms in Gram-Negative Bacteria.
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DOI：
10.1038/s42003-023-05302-2
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发表时间：
2023-09-13
影响因子：
5.9
通讯作者：
McCarthy, Ronan R.
中科院分区：
文献类型：
--
作者：
Gadar, Kavita;de Dios, Ruben;Kaderabkova, Nikol;Prescott, Thomas A. K.;Mavridou, Despoina A. I.;McCarthy, Ronan R.
鲍曼不动杆菌是一种革兰氏阴性优先病原体，可以通过一系列内在和获得性耐药机制轻易地克服抗生素治疗。碳青霉烯类耐药A.鲍曼不动杆菌病在其他治疗方法已用尽的情况下主要依赖于使用粘菌素。然而，对这种最后一线药物的耐药性的出现在临床菌株中显著增加。在这项研究中，我们确定了植物化学山奈酚作为粘杆菌素活性的增效剂。当单次给药时，山奈酚对生长没有影响，但确实影响生物膜的形成。尽管如此，山奈酚与亚抑制浓度的粘菌素的共同给药使细菌暴露于代谢的阿喀琉斯之踵，由此山奈酚诱导的铁稳态失调导致细菌杀伤。我们证明，这种效果是由于芬顿的反应中断，因此，在细胞中的有毒活性氧的致命积累。此外，我们表明，这种脆弱性可以用来克服固有的和获得性粘菌素耐药的临床菌株A。baumannii和E.大肠杆菌在体外和在大蜡螟感染模型中。总的来说，我们的研究结果提供了一个原理证明，即靶向铁稳态是一个有前途的策略，用于提高粘菌素的疗效和克服粘菌素耐药感染。植物化学物质山奈酚通过铁稳态失调降低粘菌素对病原体鲍氏不动杆菌的最小抑制浓度，这反过来又导致细胞中活性氧的致命积累。
Acinetobacter baumannii 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 A. baumannii 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 A. baumannii and E. coli in vitro and in the Galleria mellonella 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. The phytochemical kaempferol reduces the minimum inhibitory concentration of colistin against the pathogen Acinetobacter baumannii by dysregulating iron homeostasis, which in turn causes a lethal accumulation of reactive oxygen species in cells.
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影响因子：
4.5
作者：
Andrade FF;Silva D;Rodrigues A;Pina-Vaz C
通讯作者：
Pina-Vaz C
DOI：
10.1073/pnas.1611594113
发表时间：
2016-10-11
影响因子：
11.1
作者：
Boll, Joseph M.;Crofts, Alexander A.;Trent, M. Stephen
通讯作者：
Trent, M. Stephen
影响因子：
4.9
作者：
Beceiro, Alejandro;Llobet, Enrique;Woodford, Neil
通讯作者：
Woodford, Neil
影响因子：
6
作者：
del Valle, Pilar;Rosario Garcia-Armesto, Maria;Rua, Javier
通讯作者：
Rua, Javier
影响因子：
3.5
作者：
Catel-Ferreira, Manuella;Marti, Sara;De, Emmanuelle
通讯作者：
De, Emmanuelle