Carbon Monoxide Gas Is Not Inert, but Global, in Its Consequences for Bacterial Gene Expression, Iron Acquisition, and Antibiotic Resistance.
Carbon Monoxide Gas Is Not Inert, but Global, in Its Consequences for Bacterial Gene Expression, Iron Acquisition, and Antibiotic Resistance.
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DOI：
10.1089/ars.2015.6501
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发表时间：
2016-06-10
影响因子：
6.6
通讯作者：
Poole RK
中科院分区：
文献类型：
--
作者：
Wareham LK;Begg R;Jesse HE;Van Beilen JW;Ali S;Svistunenko D;McLean S;Hellingwerf KJ;Sanguinetti G;Poole RK
目的：一氧化碳是一种呼吸道毒物和气体信号分子。尽管 CO 释放分子 (CORM) 在哺乳动物中以时间和空间特异性释放 CO，并且是经过验证的抗菌剂，但我们不了解 CO 毒性的模式。我们的目的是在不使用 CORM 干预的情况下探索 CO 气体本身对细菌生理学和基因表达的影响。结果：我们使用严格控制的恒化器条件，并将转录组数据集与统计模型相结合，以揭示 CO 的全局影响。已知 CO 会抑制细菌呼吸，我们发现编码能量转换途径的基因表达受到全局调节因子 Fnr、Arc 和 PdhR 的显着影响。在有氧条件下，ArcA（反应调节剂）会短暂磷酸化并积累丙酮酸，类似于厌氧条件。与铁获取、含硫氨基酸和精氨酸代谢有关的基因都受到干扰。通过调节转录因子 Fur 的活性证实，与铁相关的整体变化可能是铁载体排泄增强、细胞内铁池减少以及 CO 攻击细菌对金属螯合剂敏感性的基础。尽管 CO 气体（与 H2S 和 NO 不同）对抗生素的保护作用很小，但钌 CORM 是抗生素活性的有效佐剂。创新：这是对全球细菌对 CO 反应的首次详细探索，揭示了意想不到的目标，对 CORM 的治疗应用具有影响。结论：这项工作揭示了细菌对 CO 反应的复杂性，并为了解 CORM、血红素加氧酶活性或环境来源的 CO 影响提供了基础。抗氧化剂。氧化还原信号。 24, 1013–1028。
Aims: Carbon monoxide is a respiratory poison and gaseous signaling molecule. Although CO-releasing molecules (CORMs) deliver CO with temporal and spatial specificity in mammals, and are proven antimicrobial agents, we do not understand the modes of CO toxicity. Our aim was to explore the impact of CO gas per se, without intervention of CORMs, on bacterial physiology and gene expression. Results: We used tightly controlled chemostat conditions and integrated transcriptomic datasets with statistical modeling to reveal the global effects of CO. CO is known to inhibit bacterial respiration, and we found expression of genes encoding energy-transducing pathways to be significantly affected via the global regulators, Fnr, Arc, and PdhR. Aerobically, ArcA—the response regulator—is transiently phosphorylated and pyruvate accumulates, mimicking anaerobiosis. Genes implicated in iron acquisition, and the metabolism of sulfur amino acids and arginine, are all perturbed. The global iron-related changes, confirmed by modulation of activity of the transcription factor Fur, may underlie enhanced siderophore excretion, diminished intracellular iron pools, and the sensitivity of CO-challenged bacteria to metal chelators. Although CO gas (unlike H2S and NO) offers little protection from antibiotics, a ruthenium CORM is a potent adjuvant of antibiotic activity. Innovation: This is the first detailed exploration of global bacterial responses to CO, revealing unexpected targets with implications for employing CORMs therapeutically. Conclusion: This work reveals the complexity of bacterial responses to CO and provides a basis for understanding the impacts of CO from CORMs, heme oxygenase activity, or environmental sources. Antioxid. Redox Signal. 24, 1013–1028.