The Staphylococcal-specific Antibiotic Debio 1450 Minimizes Disturbance to the Gut Microbiota in Mice

Background:

Debio 1450 is an antimicrobial agent candidate currently in Phase II clinical development for intravenous and oral treatment of staphylococcal infections. It specifically targets staphylococcal species through inhibition of staphylococcal FabI, an enzyme, essential for fatty acid synthesis in this genus¹. The aim of the present study was to compare the effects of Debio 1450 versus 3 broad-spectrum antibiotics commonly used in the clinic to treat staphylococcal infections on the mouse intestinal microbiota.

Methods:

Groups of 5 CD-1 mice were treated orally for 10 days with either Debio 1450 65 mg/kg BID, clindamycin 100 mg/kg BID, linezolid 100 mg/kg BID, moxifloxacin 65 mg/kg QD, or vehicle BID. Stool samples were collected from each animal in a sterile manner by abdominal massage 2 days before (baseline), during treatment (days 2 and 10) and 7 days after the end of treatment. Total DNA was extracted from stool samples. The hypervariable V3 and V4 regions of the 16S rRNA gene were sequenced using Illumina MiSeq platform and taxonomic classification of sequences was obtained using a bioinformatics pipeline based on Mothur software².

Results:

No intergroup differences were seen at baseline in the taxonomic composition. While radical changes in the microbiota were observed for all mice in response to the 3 broad-spectrum antibiotics over the course of treatment and post-treatment, there were no statistically significant differences in the microbiota composition between the Debio 1450-group and the vehicle-group on phylum level. For example, during the clindamycin and linezolid treatments, bacterial composition was shifted from Bacteroidetes and Firmicutes to a large proportion of Proteobacteria. Differences in the taxonomy distribution appeared as soon as day 2 and persisted for up to 7 days post-treatment in the 3 broad-spectrum antibiotics groups.

Conclusion:

While the three broad-spectrum comparator antibiotics led to major profile variations, Debio 1450 did not cause relevant changes in the gut microbiota. This result supports the development of targeted antibiotherapy to treat staphylococcal infections. It is hoped to reduce antibiotic-associated complications such as diarrhea, colitis, C. difficile infections or candidiasis.

Ref:

¹ Lu, et al. Acc Chem Res (2008)

² Schloss, et al. Appl Environ Microbiol (2009)