Environmental bacteria as a reservoir of novel antibiotic resistance mechanisms

环境细菌作为新型抗生素耐药机制的储存库

• 批准号: 2598276
• 金额: --
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2598276
• 关键词: Environmental; bacteria; reservoir; novel; antibiotic

Streptomycetes are undisputedly the most important producers of antibiotics in the soil. Despite this, little is known about how they themselves resist antimicrobials. This is concerning as some of the most problematic resistance mechanisms we now see in the clinic have originated in the natural environment. It is therefore important to gain a better understanding of the arsenal of resistance mechanisms in the soil that have yet to be discovered. Antimicrobial peptides (AMPs) have recently received much attention as promising new drugs. They are produced by low-GC Gram-positive firmicutes, which often share the soil habitat with streptomycetes. It is well-understood how firmicute bacteria resist AMPs, but the corresponding genes appear to be conspicuously absent from streptomycetes. Streptomyces venezuelae possesses a striking degree of resistance against AMPs. Sensitive mutants of this bacterium have been isolated, but none of the mutations are located in known antimicrobial resistance genes.The project aims to identifying the gene(s) responsible for AMP resistance in S. venezuelae, determine how they are regulated, their wider distribution in actinomycetes, and the role of AMPs in the ecology of S. venezuelae. During the first year, this will entail selection of candidate genes responsible for AMP resistance using DNA and RNA sequencing data previously obtained from sensitive mutants by chemical mutagenesis. Candidate genes will then be transduced into sensitive mutants to identify which genes reinstate the resistant phenotype. Once the genes responsible for resistance have been identified, further exploratory work will seek to identify the mechanism by which these genes enable resistance. This is likely to include computational modelling of the mechanism. The prevalence and relevance of the newly identified resistance mechanisms in the environment will then be investigated using genomics and community interaction approaches. Understanding the composition of identified genes in the soil community will facilitate future predictions of the potential route by which resistance genes may transfer into clinical pathogenic strains.

链霉菌无疑是土壤中最重要的抗生素生产者。尽管如此，人们对它们自身如何抵抗抗菌素知之甚少。这是令人担忧的，因为我们现在在临床中看到的一些最有问题的耐药机制起源于自然环境。因此，重要的是要更好地了解尚未发现的土壤中的抗性机制库。抗菌肽（Antimicrobial peptides, AMPs）是近年来备受关注的新兴药物。它们是由低gc革兰氏阳性厚壁菌产生的，这些厚壁菌通常与链菌共享土壤栖息地。众所周知，厚壁菌是如何抵抗AMPs的，但在链霉菌中却明显缺乏相应的基因。委内瑞拉链霉菌对抗菌肽具有显著的抗性。已分离出这种细菌的敏感突变体，但没有一个突变位于已知的抗微生物药物耐药性基因中。该项目旨在确定委内瑞拉葡萄球菌中AMP抗性的基因，确定它们是如何被调节的，它们在放线菌中的更广泛分布，以及AMP在委内瑞拉葡萄球菌生态中的作用。在第一年，这将需要使用先前通过化学诱变从敏感突变体中获得的DNA和RNA测序数据来选择负责AMP抗性的候选基因。然后将候选基因转导成敏感突变体，以确定哪些基因恢复抗性表型。一旦确定了产生抗性的基因，进一步的探索性工作将寻求确定这些基因使抗性产生的机制。这可能包括对机制的计算建模。然后将使用基因组学和社区相互作用方法调查环境中新发现的抗性机制的患病率和相关性。了解土壤群落中已鉴定基因的组成将有助于未来预测抗性基因转移到临床致病菌株的潜在途径。