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

结直肠癌（CRC）是全球癌症相关死亡的第二大原因。肠道微生物群与该疾病的病因联系越来越紧密，并且已确定与口腔病原体丰度的强阶段依赖相关性以及与粘膜共生菌的抗相关性。越来越多的证据表明，微生物组也能够影响许多已建立的细胞毒性疗法的治疗效果和毒性。这意味着肠道微生物组可以被调节来消除免疫和化疗的毒性或提高其疗效，甚至可以作为一个新的治疗靶点。然而，目前的微生物组修饰策略，如预益生菌和益生菌治疗、抗生素治疗、粪便微生物群移植和微生物工程，尚未被广泛探索治疗潜力。合成生物学应用工程原理和数学模型来开发新的生物疗法。细菌素是由某些种类的细菌自然产生的小型抗菌肽，用于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）。细菌素可以具有高度特异性或广谱性，并且可以以模块化方式组合以创建独特的抗菌剂。我们的假设是细菌素可以用于CRC粘膜微生物组的精密工程，从而影响细胞毒性化疗的疗效和毒性。合成生物学的工具将使针对特定细菌物种的菌株快速工程成为可能。我们在许多模型系统中部署这些疗法，目的是为未来的临床试验提供基础。这种工程方法将促进干预措施的发展，这些干预措施可以与化疗药物共同递送，从而降低毒性，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.