The molecular basis of multiple herbicide resistance in grass weeds

目前，全球粮食生产和生物燃料生产对谷物的需求，再次强调需要科学和技术来支持可持续和高产的可耕地农业。高效谷物生产的一个关键组成部分是仔细使用化学控制来抑制竞争杂草。然而，在过去的40年里，除草剂的密集使用已经选择了对主要谷物如小麦中使用的选择性杀禾本科剂（杀草剂）具有抗性的禾本科杂草种群。1982年，在英国的一个黑草种群中确定了一种新的抗性形式，这种抗性形式扩展到了小麦和大麦中被许可用于控制的所有类别的除草剂。从那时起，多重除草剂抗性（MHR）的发生率变得更加频繁，并在许多其他有害的禾本科杂草中也得到了发展。在极端情况下，MHR杂草会使作物枯萎，只能通过非可持续的做法（如深耕）来控制。最近，我们已经表明，谷胱甘肽转移酶（GST）称为AmGSTF1是病原体的MHR在黑草。AmGSTF1蛋白在其他植物中的表达导致它们在MHR黑草中观察到的抗氧化防御中采取相同的不寻常变化。MHR植物表现为它们受到氧化胁迫，这反过来导致它们对包括除草剂在内的化学品更具抗性。通常GST的功能是代谢除草剂，因此家族成员在协调MHR中的调节作用是出乎意料的。利用我们的药物化学知识，我们已经确定了一类选择性结合并抑制AmGSTF1的化学物质。如果这些增效剂与除草剂共同施用，它们可以恢复MHR杂草的化学控制，因此这一发现可能是作物保护中极其重要的发现。我们现在建议与农业化学公司先正达（Syngenta）合作，该公司的除草剂发现中心位于英国，以确定AmGSTF1如何通过使用这些化学抑制剂破坏其功能来导致黑草中的MHR。我们还想了解抑制剂如何选择性地与AmGSTF1结合，这样我们就可以合理地设计新的增效剂，并确定这些化合物是否也以类似的方式在其他禾本科杂草中发挥作用。最后，MHR可能有我们想要研究的积极方面。MHR反应的进化不太可能仅仅是为了对抗除草剂。相反，我们认为AmGSTF1信号是谷物和禾本科杂草天然抗氧化应激反应系统的重要组成部分。为了测试这种可能性，我们将在其他植物中表达amgstf1基因，并确定它们的生物化学变化是否使它们对不利的环境条件更具抵抗力。在我们的研究结束时，我们打算了解AmGSTF1如何发挥作用以调节禾本科杂草中的MHR的基本生物学，开发了新的化学物质来阻断其活性并恢复除草剂敏感性，并确定了一种潜在的新途径来工程作物的胁迫耐受性。最后，我们的项目可能会对动物和微生物对药物和农药产生多重耐药性的机制产生新的见解。

The current demands on global cereal production for food and biofuels production have placed renewed emphasis on the need for science and technologies to support sustainable and high yielding arable agriculture. A key component of efficient cereal production is the careful use of chemical control to suppress competing weeds. However, over the last 40 years the intensive use of herbicides has selected for populations of grass weeds which are resistant to selective graminicides (grass-killers) used in major cereals like wheat. In 1982 a new form of resistance was determined in a black-grass population in the UK which extended to all classes of herbicides licensed for its control in wheat and barley. Since then, incidences of multiple herbicide resistance (MHR) have become more frequent and have also developed in many other pernicious grass weeds. In extreme cases MHR weeds can devastate crops and can only be controlled by non-sustainable practices like deep ploughing. Recently, we have shown that a glutathione transferase (GST) termed AmGSTF1 is the causative agent of MHR in black-grass. Expression of the AmGSTF1 protein in other plants causes them to adopt the same unusual changes in their antioxidant defences seen in MHR black-grass. MHR plants behave as it they are being oxidatively stressed and this is n turn results in them becoming more resistant to chemicals including herbicides. Normally GSTs function to metabolize herbicides so a regulatory role for a family member in co-ordinating MHR was unexpected. Using our knowledge of medicinal chemistry, we have identified a class of chemicals which selectively bind to and inhibit AmGSTF1. If these synergists are co-applied with herbicides they can restore chemical control in MHR weeds and so this discovery is potentially an extremely important discovery in crop protection. We now propose to work with the agrochemical company Syngenta, which has its herbicide discovery centre located in the UK, to determine how AmGSTF1 causes MHR in black-grass by using these chemical inhibitors to disrupt its function. We also want to understand how the inhibitors bind selectively to AmGSTF1 so we can rationally design new synergists and establish if these compounds also work in a similar way in other grass weeds. Finally, there may be a positive aspect to MHR which we want to study. It is unlikely that the MHR response has evolved just to counteract herbicides. Instead, we suggest that AmGSTF1 signaling is an important part to the natural antioxidant stress response system of cereals and grass weeds. To test this possibility we will express the amgstf1 gene in other plants and determine whether or not the resulting changes in their biochemistry make them more resistant to adverse environmental conditions. At the conclusion of our studies we intend to understand the fundamental biology behind how AmGSTF1 functions to regulate MHR in grass weeds, have developed novel chemistries to block its activity and restore herbicide sensitivity and determined a potential new route to engineering stress tolerance in crops. Finally, our project may shed new insights into the mechanisms underlying multiple resistance to drugs and pesticides which have developed in animals and microbes.