An engineered live biotherapeutic for the prevention of antibiotic-induced dysbiosis
An engineered live biotherapeutic for the prevention of antibiotic-induced dysbiosis
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一种用于预防抗生素引起的生态失调的工程活生物疗法
DOI：
10.1038/s41551-022-00871-9
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发表时间：
2022-04-11
影响因子：
28.1
通讯作者：
Collins, James J.
中科院分区：
文献类型：
--
作者：
Cubillos-Ruiz, Andres;Alcantar, Miguel A.;Collins, James J.
一株乳酸乳球菌经过工程改造，通过分泌和细胞外组装异二聚体β-内酰胺酶来利他性降解β-内酰胺抗生素，从而防止氨苄青霉素治疗小鼠肠道中的生态失调。抗生素诱导的肠道微生物群改变与许多代谢和炎症性疾病有关，增加继发感染的风险，并有助于出现抗生素耐药性。在这里，我们报告了乳酸乳球菌工程菌株的设计和体内性能，该工程菌株通过分泌和胞外组装异二聚体β-内酰胺酶来利他降解广泛使用的广谱抗生素β-内酰胺（其破坏肠道中的细菌）。工程改造的β-内酰胺酶表达系统不赋予生产细胞β-内酰胺抗性，并且通过遗传上不连锁的双基因生物合成策略编码，其不易于通过水平基因转移传播。在肠胃外氨苄青霉素治疗的小鼠模型中，口服补充工程化活生物素最小化了肠道生态失调而不影响血清中的氨苄青霉素浓度，阻止了肠道微生物组中抗微生物剂抗性基因的富集，并防止了对艰难梭菌的定殖抗性的丧失。安全降解肠道中抗生素的工程活生物治疗剂可能是预防生态失调及其相关病理的合适策略。
A strain of Lactococcus lactis engineered to altruistically degrade beta-lactam antibiotics through the secretion and extracellular assembly of a heterodimeric beta-lactamase prevented dysbiosis in the gut of mice treated with ampicillin.Antibiotic-induced alterations in the gut microbiota are implicated in many metabolic and inflammatory diseases, increase the risk of secondary infections and contribute to the emergence of antimicrobial resistance. Here we report the design and in vivo performance of an engineered strain of Lactococcus lactis that altruistically degrades the widely used broad-spectrum antibiotics beta-lactams (which disrupt commensal bacteria in the gut) through the secretion and extracellular assembly of a heterodimeric beta-lactamase. The engineered beta-lactamase-expression system does not confer beta-lactam resistance to the producer cell, and is encoded via a genetically unlinked two-gene biosynthesis strategy that is not susceptible to dissemination by horizontal gene transfer. In a mouse model of parenteral ampicillin treatment, oral supplementation with the engineered live biotherapeutic minimized gut dysbiosis without affecting the ampicillin concentration in serum, precluded the enrichment of antimicrobial resistance genes in the gut microbiome and prevented the loss of colonization resistance against Clostridioides difficile. Engineered live biotherapeutics that safely degrade antibiotics in the gut may represent a suitable strategy for the prevention of dysbiosis and its associated pathologies.