Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model.
Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model.
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DOI：
10.1016/j.celrep.2021.110202
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发表时间：
2022-01-11
期刊：
影响因子：
8.8
通讯作者：
McDevitt, Christopher A.
中科院分区：
文献类型：
--
作者：
Brazel, Erin B.;Tan, Aimee;Neville, Stephanie L.;Iverson, Amy R.;Udagedara, Saumya R.;Cunningham, Bliss A.;Sikanyika, Mwilye;De Oliveira, David M. P.;Keller, Bernhard;Bohlmann, Lisa;El-Deeb, Ibrahim M.;Ganio, Katherine;Eijkelkamp, Bart A.;McEwan, Alastair G.;von Itzstein, Mark;Maher, Megan J.;Walker, Mark J.;Rosch, Jason W.;McDevitt, Christopher A.
肺炎链球菌是社区获得性细菌性肺炎的主要病因，青霉素和多重耐药率分别超过80%和40%。先天免疫反应产生多种抗菌剂来控制感染，包括锌应激。在这里，我们描述了锌中毒对S。pneumoniae，观察中心碳代谢、脂质生物合成和肽聚糖生物合成的破坏。关键肽聚糖生物合成酶GlmU的表征表明对锌抑制的敏感性。破坏唯一的锌外排途径czcD，使S。肺炎链球菌对β-内酰胺类抗生素高度敏感。为了在野生型菌株中失调锌稳态，我们研究了对人类安全使用的离子载体5，7-二氯-2-[（二甲氨基）甲基]喹啉-8-醇（PBT 2）。PBT 2使野生型S.肺炎菌株对一系列抗生素敏感。使用侵袭性氨苄青霉素耐药菌株，我们在鼠肺炎感染模型中证明了PBT 2+氨苄青霉素治疗的功效。这些发现为打破多重耐药链球菌的抗生素耐药性提供了一种治疗方法。肺炎。抗生素耐药性对肺炎链球菌引起的肺炎的治疗构成越来越大的威胁。Brazel等人展示了锌如何用于打破细菌的抗生素耐药性。他们重新利用人类安全使用的锌转运离子载体5，7-二氯-2-[（二甲氨基）甲基]喹啉-8-醇（PBT 2），以打破肺部感染期间的细菌耐药性，并恢复氨苄青霉素治疗的疗效。
Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multidrug-resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection, including zinc stress. Here, we characterize the impact of zinc intoxication on S. pneumoniae, observing disruptions in central carbon metabolism, lipid biogenesis, and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU indicates a sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, renders S. pneumoniae highly susceptible to β-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human-use ionophore 5,7-dichloro-2-[(dimethylamino) methyl]quinolin-8-ol (PBT2). PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2 + ampicillin treatment. These findings present a therapeutic modality to break antibiotic resistance in multidrug-resistant S. pneumoniae. Antibiotic resistance is a growing threat to treatment of pneumonia caused by Streptococcus pneumoniae. Brazel et al. show how zinc can be used to break bacterial antibiotic resistance. They repurpose the safe-for-human-use zinc transporting ionophore, 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (PBT2), to break bacterial drug resistance during lung infection and restore the efficacy of ampicillin treatment.
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影响因子：
5.3
作者：
Jen, Freda E. -C.;Everest-Dass, Arun V.;Jennings, Michael P.
通讯作者：
Jennings, Michael P.
影响因子：
3.1
作者：
BRILES, DE;CRAIN, MJ;YOTHER, J
通讯作者：
YOTHER, J
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
Cowtan, K
影响因子：
6.7
作者：
Eijkelkamp, Bart A.;Morey, Jacqueline R.;Mcdevitt, Christopher A.
通讯作者：
Mcdevitt, Christopher A.
影响因子：
4.8
作者：
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通讯作者：
Cook, Gregory M.