Carbon monoxide and metal carbonyl CO-releasing molecules (CORMs) as novel antimicrobial agents - a systems approach to cellular targets and effects

该项目关注一氧化碳（CO）如何影响细菌。一氧化碳是一种众所周知的燃料、污染物和呼吸道毒物。每年都有许多意外死亡和自杀事件是CO中毒的结果。然而，CO在生物学和医学中也具有令人惊讶但非常重要的重要作用。它被一些环境细菌用作能量供应，这些细菌能够感知气体的存在并以适当的方式处理它。CO也通过酶（血红素加氧酶）在体内自然产生。这种CO具有有效的生物学作用，包括改善血管张力和其他细胞保护功能。令人惊讶的是，CO在治疗小鼠细菌感染方面显示出有希望的效果。例如，CO减少脾脏中铜绿假单胞菌的计数并增加动物的存活率。因此，CO在抗菌过程中起着重要作用，最近的数据表明，CO给药可能是一种临床有用的干预措施。但是，我们不知道CO是如何工作的。该项目将使我们对CO气体和新设计的可用于递送CO（CORM）的分子的抗菌活性模式的理解取得重大进展。我们将比较CO作为气体和通过施用所选CORM的抑制活性。同时，将开发一氧化碳对大肠杆菌细菌的影响的计算模型，当新的实验结果出现时，该模型能够得到改进。一个主要的重点将是测试的假设，即CO是一个竞争性抑制剂与氧气和氧气浓度周围的细菌是CORM有效性的主要决定因素。我们将确定每种细菌呼吸酶对CO的敏感性，这是CO抑制的主要目标。我们将首次确定CO和CORM如何进入细菌，并试图了解它们对基因和蛋白质的影响的全部程度。这项研究将在改善细菌感染的控制方面产生长期效益，并可能用于治疗人类疾病，特别是由耐药性细菌引起的疾病。

This project is concerned with how carbon monoxide (CO) affects bacteria. CO is a gas that is well known as a fuel, pollutant, and respiratory poison. Numerous accidental deaths and suicides are the result of CO poisoning each year. However, CO also has surprising but very important essential roles in biology and medicine. It is used as an energy supply by some environmental bacteria, which are able to sense the presence of the gas and switch on appropriate ways to deal with it. CO is also produced naturally in the body by enzymes (haem oxygenases). This CO has potent biological effects, including improvement of vascular tone and other cell protecting functions. Surprisingly, CO has shown promising effects on treating bacterial infections in mice. For example, CO decreases counts of Pseudomonas aeruginosa in the spleen and increases survival of the animals. So, CO plays an important role in antimicrobial processes and recent data show that CO administration may be a clinically useful intervention. However, we do not understand how CO works. This project will make significant advances in our understanding of the mode of antibacterial activity of CO gas and newly designed molecules that can be used to deliver CO (CORMs). We will compare the inhibitory activities of CO applied as a gas and via administration of selected CORMs. In parallel, a computational model of the impact of CO on the bacterium Escherichia coli will be developed, capable of being refined when new experimental results become available. A major focus will be testing the hypothesis that CO is a competitive inhibitor with oxygen and that oxygen concentration around the bacterium is a prime determinant of CORM effectiveness. We will determine the sensitivity to CO of each of the bacterium's respiratory enzymes, prime targets for CO inhibition. For the first time, we will determine how CO and CORMs enter bacteria and try to understand the full extent of their effects on genes and proteins. This research will have long-term benefits in improving the control of bacterial infections and might be used to treat disease in humans, especially diseases caused by antibiotic-resistant bacteria.