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 β-lactams (which disrupt commensal bacteria in the gut) through the secretion and extracellular assembly of a heterodimeric β-lactamase. The engineered β-lactamase-expression system does not confer β-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.

抗生素引起的肠道菌群改变与许多代谢性疾病和炎症性疾病有关，会增加继发感染的风险，并导致出现抗生素耐药性。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通过异二聚体 β-内酰胺酶的分泌和细胞外组装，无私地降解广泛使用的广谱抗生素 β-内酰胺（破坏肠道中的共生细菌）。工程化的 β-内酰胺酶表达系统不会赋予生产细胞 β-内酰胺抗性，并且通过遗传上不相关的双基因生物合成策略进行编码，该策略不易通过水平基因转移传播。在肠外氨苄青霉素治疗的小鼠模型中，口服补充工程化的活生物治疗药物可在不影响血清氨苄青霉素浓度的情况下最大限度地减少肠道菌群失调，防止肠道微生物组中抗菌素耐药基因的富集，并防止对艰难梭菌的定植耐药性丧失. 能够安全降解肠道中抗生素的工程化活生物治疗剂可能是预防生态失调及其相关病症的合适策略。