CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)3Cl(glycinate)] Actions on a Heme-Deficient Mutant of Escherichia coli.
CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)3Cl(glycinate)] Actions on a Heme-Deficient Mutant of Escherichia coli.
复制标题
DOI：
10.1089/ars.2014.6151
复制
发表时间：
2015-07-10
影响因子：
6.6
通讯作者：
Poole RK
中科院分区：
文献类型：
--
作者：
Wilson JL;Wareham LK;McLean S;Begg R;Greaves S;Mann BE;Sanguinetti G;Poole RK
目的：一氧化碳释放分子正在开发中，最终目标是安全地利用一氧化碳的临床治疗潜力，包括在抗菌治疗中的应用。血红素通常被认为是一氧化碳和球茎的主要目标，所以我们使用缺乏血红素的细菌，应用细胞、转录和生化工具来验证这一假说。结果：CORM-3[Ru(CO)3CL(甘氨酸)]能很好地穿透大肠杆菌HEMA细菌，对这些细菌和乳酸乳球菌有抑制作用，即使它们缺乏所有可检测到的血红素。转录分析，结合转录因子活性的数学模型，揭示了HEMA细菌对CORM-3的反应是多方面的，但其特征是铁获取和利用机制、全球胁迫反应和锌管理过程的表达显著增加。细胞膜受到CORM-3的干扰。创新：这项工作首次证明了CORM-3(在较小程度上也是其灭活的对应物)具有除血红素以外的多个细胞靶点。充分了解球茎的活动对于了解它们的毒性作用至关重要。结论：这项工作加深了我们对CORM-3在细菌中的关键靶标的理解，并提出了广泛报道的抗菌作用不能归因于CO的经典生化靶标的可能性。这是开发潜力的关键一步，已经证明，在抗菌治疗中使用优化的球茎。抗氧化剂。氧化还原信号。23,148-162。
Aims: Carbon monoxide-releasing molecules (CORMs) are being developed with the ultimate goal of safely utilizing the therapeutic potential of CO clinically, including applications in antimicrobial therapy. Hemes are generally considered the prime targets of CO and CORMs, so we tested this hypothesis using heme-deficient bacteria, applying cellular, transcriptomic, and biochemical tools. Results: CORM-3 [Ru(CO)3Cl(glycinate)] readily penetrated Escherichia coli hemA bacteria and was inhibitory to these and Lactococcus lactis, even though they lack all detectable hemes. Transcriptomic analyses, coupled with mathematical modeling of transcription factor activities, revealed that the response to CORM-3 in hemA bacteria is multifaceted but characterized by markedly elevated expression of iron acquisition and utilization mechanisms, global stress responses, and zinc management processes. Cell membranes are disturbed by CORM-3. Innovation: This work has demonstrated for the first time that CORM-3 (and to a lesser extent its inactivated counterpart) has multiple cellular targets other than hemes. A full understanding of the actions of CORMs is vital to understand their toxic effects. Conclusion: This work has furthered our understanding of the key targets of CORM-3 in bacteria and raises the possibility that the widely reported antimicrobial effects cannot be attributed to classical biochemical targets of CO. This is a vital step in exploiting the potential, already demonstrated, for using optimized CORMs in antimicrobial therapy. Antioxid. Redox Signal. 23, 148–162.
登录
查看更多内容
DOI：
10.1073/pnas.95.18.10378
发表时间：
1998-09-01
影响因子：
11.1
作者：
Gardner, PR;Gardner, AM;Salzman, AL
通讯作者：
Salzman, AL
影响因子：
20.1
作者：
Clark, JE;Naughton, P;Motterlini, R
通讯作者：
Motterlini, R
大肠杆菌K-12的构造框架，单基因敲除突变体：Keio Collection。
影响因子：
9.9
作者：
通讯作者：
--
影响因子：
5.8
作者：
Asif, H. M. Shahzad;Rolfe, Matthew D.;Sanguinetti, Guido
通讯作者：
Sanguinetti, Guido
影响因子：
38.9
作者：
Foresti, Roberta;Bani-Hani, Mohamed G.;Motterlini, Roberto
通讯作者：
Motterlini, Roberto