Rhodococcus jostii RHA1: biology and applications

细菌在很多方面对人类都很重要。最重要的是，我们的健康和生存取决于我们体内和体表的细菌数量。我们在许多行业中使用细菌，如食品、卫生、化学和环境清理；许多微生物产品被常规使用。其中最重要的是抗生素，它是传染病治疗的基石。不幸的是，抗生素的有效寿命受到微生物对它们产生耐药性的能力的限制，因此需要找到新的有效的抗生素。这一建议将利用分子遗传学的进步来发现和生产新型抗生素。我们使用的大多数抗生素都是由放线菌家族的细菌产生的，最近的基因组测序工作表明，该属的大多数菌株有可能产生20种或更多的抗生素，然而这些化合物是不可用的，因为它们是通过放线菌菌株的“沉默”或“隐”途径产生的。获得这些化合物的一种方法是从它们的天然宿主中去除生物合成簇，并使用可定制的表达系统在异源宿主中制造它们，这些系统可以大量制造这些化合物。我们选择红球菌作为这样的宿主；这些细菌生长迅速，很容易被改造成生产抗生素的健壮宿主。为了实现这一目标，我们将对不同的红球菌菌株进行详细的生长研究，以优化生长条件，并通过各种方法（如“核糖体工程”）提高它们生产抗生素的能力。这种可靠的宿主菌株的收集将允许发现许多新的化合物，这些化合物应该具有有用的抗生素和其他治疗应用。

Bacteria are very important to humankind in many respects. Most importantly, our health and survival is dependent on the bacterial populations in and on our body. We employ bacteria in many industries such as food, health, chemical, and environmental clean-up; many microbial products are used routinely. Among the most important are antibiotics that are the cornerstone of infectious disease treatment. Unfortunately, the useful lifetime of antibiotics is limited by the ability of microbes to become resistant to them and there is a need to find new and effective antibiotics. This proposal will take advantage of advances in molecular genetics to discover and produce novel types of antibiotics. Most of the antibiotics we use are produced by bacteria of the Actinomycete family and recent work on genome sequencing has shown that most strains of this genus have the potential to produce 20 or more antibiotics, however these compounds are not available because they are made by "silent" or "cryptic" pathways in Actinomycete strains. One approach to obtaining these compounds is to remove the biosynthetic clusters from their natural host and make them in heterologous hosts using defined expression systems that can be tailored to make the compounds in quantity. We have chosen to use Rhodococci as such a host; these bacteria grow fast and can be easily engineered to make robust hosts for antibiotic production. In order to achieve this goal we will to carry out detailed growth studies of different Rhodococcal strains to optimise growth conditions and to improve their abilities to produce antibiotics by various methods such as "ribosome engineering" The availability of such a collection of reliable host strains will permit the discovery of many novel compounds that should have useful antibiotic and other therapeutic applications.