Engineering novel bacterial therapies for targeting microbes associated with chemotherapy response and toxicity

结直肠癌(CRC)是全球第二大癌症相关死亡原因。肠道微生物组在这种疾病的病因中越来越多地被联系在一起，并且与口腔致病菌的丰度有很强的阶段相关性，与粘膜共生细菌的反相关性已经被发现。有新的证据表明，在许多已建立的细胞毒疗法中，微生物组也能够影响治疗效果和毒性。这意味着可以通过调节肠道微生物群来消除免疫和化疗的毒性或提高其疗效，甚至可以作为新的治疗靶点。然而，目前微生物组修饰的策略，如前和益生菌治疗、抗生素治疗、粪便微生物区系移植和微生物工程的治疗潜力尚未得到广泛的探索。合成生物学将工程原理和数学模型应用于新的生物治疗药物的开发。细菌素是一种小的抗菌肽，由某些种类的细菌自然产生，目的是针对竞争对手，并允许建立菌落。Nisin是研究最多的一种，被用作食品防腐剂(E234)。细菌素可以是高度特异的，也可以具有广泛的光谱，并可以以模块化的方式结合在一起，以创建独特的抗菌剂。我们的假设是，细菌素可以用于对结直肠癌粘膜微生物组的精确工程，以影响细胞毒化疗的疗效和毒性。合成生物学的工具将使菌株的快速工程能够针对特定的细菌物种。我们将这些疗法部署在一些模型系统中，目的是为未来的临床试验提供基础。这种工程方法将有助于开发可与化疗药物联合提供的干预措施，从而减少毒性、安全增加剂量，并最终提高疗效。

Colorectal cancer (CRC) is the second leading cause of cancer related deaths world-wide. The gut microbiome is increasingly linked in the causation of this disease and strong stage-dependent correlations with the abundance of oral pathobionts and anti-correlations with mucosal commensal bacteria have been identified. There is emerging evidence that the microbiome is also able to influence therapeutic efficacy and toxicity in many established cytotoxic therapies. The implication of this is that the gut microbiome can be modulated to abrogate the toxicity of both immuno- and chemotherapy or improve its efficacy, and that it may even serve as a novel therapeutic target. However, current strategies for microbiome modification such as pre- and probiotic therapy, antibiotic therapy, faecal microbiota transplantation and microbial engineering have yet to be widely explored for therapeutic potential.Synthetic biology applies engineering principles and mathematical modelling to the development of new biotherapeutics. Bacteriocins are small antimicrobial peptides that are naturally produced by certain species of bacteria to target competitors and allow for the establishment of colonies. Nisin is the amongst the most studied and is used as a food preservative (E234). Bacteriocins can be highly specific or have a broad spectrum and can be combined in a modular fashion to create unique antimicrobial agents. Our hypothesis is that bacteriocins can be used for precision engineering of the CRC mucosal microbiome to influence the efficacy and toxicity of cytotoxic chemotherapy. The tools of synthetic biology will enable the rapid engineering of strains to target specific bacterial species. We deploy these therapies in a number of model systems with an aim to providing the foundation for future clinical trials. This engineering approach will facilitate the development of interventions that can be co-delivered with chemotherapy agents, allowing for a reduction in toxicity, a safe increase in dose, and ultimately improve efficacy.