Antibiotic-induced alterations in the gut microbiota are implicated in a wide range of metabolic and inflammatory diseases, as well as with the emergence of antimicrobial resistance and increased risk to secondary infections. β-lactams are the most widely used antibiotics and their broad-spectrum activity is known to cause major disruptions to commensal bacteria in the gut.
Accordingly, there is a pressing need for interventions that protect the native gut microbiota from systemically circulating β-lactams when the antibiotic action is not required in the gut. We engineered a Lactococcus lactis strain that altruistically degrades β-lactam antibiotics 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 in a genetically unlinked, two-gene biosynthesis strategy that is not susceptible to dissemination by horizontal gene transfer.
Using a mouse model of parenteral ampicillin treatment, we demonstrate that oral supplementation with our engineered live biotherapeutic product (eLBP) minimizes dysbiosis in the gut without affecting the ampicillin concentration in the serum.
The eLBP precludes the enrichment of antimicrobial resistance genes in the gut
microbiome and prevents the loss of colonization resistance against Clostridioides difficile.
The use of eLBPs that safely degrade antibiotics in the gut could represent a suitable strategy for the prevention of dysbiosis and its associated pathologies.