Engineered Probiotic for the Inhibition of Salmonella via Tetrathionate-Induced Production of Microcin H47,ACS Infectious Diseases

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Engineered Probiotic for the Inhibition of Salmonella via Tetrathionate-Induced Production of Microcin H47
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-09-20 00:00:00 , DOI: 10.1021/acsinfecdis.7b00114
Jacob D Palmer ₁ , Emma Piattelli ₂ , Beth A McCormick _{3,

4} , Mark W Silby _{2,

5} , Christopher J Brigham _{1,

5} , Vanni Bucci _{2,

4,

5}

Affiliation

Complications arising from antibiotic-resistant bacteria are becoming one of the key issues in modern medicine. Members of drug-resistant Enterobacteriaceae spp. include opportunistic pathogens (e.g., Salmonella spp.) that are among the leading causes of morbidity and mortality worldwide. Overgrowth of these bacteria is considered a hallmark of intestinal dysbiosis. Microcins (small antimicrobial peptides) produced by some gut commensals can potentially cure these conditions by inhibiting these pathogens and have been proposed as a viable alternative to antibiotic treatment. In this proof-of-concept work, we leverage this idea to develop a genetically engineered prototype probiotic to inhibit Salmonella spp. upon exposure to tetrathionate, a molecule produced in the inflamed gut during the course of Salmonella infection. We developed a plasmid-based system capable of conferring the ability to detect and utilize tetrathionate, while at the same time producing microcin H47. We transferred this plasmid-based system to Escherichia coli and demonstrated the ability of the engineered strain to inhibit growth of Salmonella in anaerobic conditions while in the presence of tetrathionate, with no detectable inhibition in the absence of tetrathionate. In direct competition assays between the engineered E. coli and Salmonella, the engineered E. coli had a considerable increase in fitness advantage in the presence of 1 mM tetrathionate as compared to the absence of tetrathionate. In this work, we have demonstrated the ability to engineer a strain of E. coli capable of using an environmental signal indicative of intestinal inflammation as an inducing molecule, resulting in production of a microcin capable of inhibiting the organism responsible for the inflammation.

中文翻译：

通过连四硫酸盐诱导产生 Microcin H47 来抑制沙门氏菌的工程益生菌

抗生素耐药细菌引起的并发症正在成为现代医学的关键问题之一。耐药肠杆菌科细菌的成员。包括机会性病原体（例如沙门氏菌属），它们是全世界发病和死亡的主要原因之一。这些细菌的过度生长被认为是肠道菌群失调的标志。一些肠道共生菌产生的小菌素（小抗菌肽）可以通过抑制这些病原体来治愈这些疾病，并已被提议作为抗生素治疗的可行替代方案。在这项概念验证工作中，我们利用这一想法开发了一种基因工程原型益生菌来抑制沙门氏菌。接触连四硫酸盐后，连四硫酸盐是沙门氏菌感染过程中发炎肠道中产生的一种分子。我们开发了一种基于质粒的系统，能够检测和利用连四硫酸盐，同时产生小菌素 H47。我们将这种基于质粒的系统转移到大肠杆菌中，并证明了工程菌株在连连硫酸盐存在的情况下在厌氧条件下抑制沙门氏菌生长的能力，而在连连硫酸盐不存在的情况下没有检测到抑制作用。在工程化大肠杆菌和沙门氏菌之间的直接竞争测定中，与不存在连四硫酸盐相比，工程化大肠杆菌在存在1 mM连四硫酸盐的情况下具有显着增加的适应性优势。在这项工作中，我们展示了改造大肠杆菌菌株的能力。大肠杆菌能够利用指示肠道炎症的环境信号作为诱导分子，从而产生能够抑制引起炎症的生物体的小菌素。

更新日期：2017-09-20

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