Profiling Of Human Microbiome Research Articles

1774. Ridinilazole (RDZ) for Clostridium difficile infection (CDI): Correlation of In Vitro Spectrum of Activity with Human Gut Microbiome Profiles from a Phase 2 Clinical Trial

BackgroundRecurrence of CDI (rCDI) is associated with perturbation of the gut microbiome during treatment with vancomycin (VAN) or metronidazole (MTZ). RDZ is a novel, targeted spectrum antibacterial under investigation to treat CDI and reduce rCDI. Here correlation of in vitro spectrum of activity with preservation of the human gut microbiome and clinical outcomes is presented.MethodsSusceptibility testing was to CLSI standards with VAN, MTZ, and fidaxomicin (FDX) comparators. The Phase 2 clinical trial was a double-blind, randomized study of 100 patients assigned 1:1 to 10 days RDZ 200 mg BID or VAN 125 mg QID treatment. Primary endpoint was sustained clinical response (SCR), defined as cure at end of therapy (EOT), and no rCDI for the next 30 days. Relative effects of RDZ and VAN on the gut microbiome were examined by sequencing 16S rDNA amplicons from stool collected at baseline, days 5, 10, 25, and end of study. Bioinformatic analyses were performed in QIIME.ResultsRDZ C. difficile (N = 50) MIC range was 0.125–0.25 μg/mL. Clostridium spp. showed varied RDZ susceptibility; C. innocuum MIC90 1 μg/mL, C. ramosum and C. perfringens MIC90 >512 μg/mL. VAN showed potent to moderate growth inhibition of all Clostridium spp. (MIC range 1–16 µg/mL). Limited RDZ activity was observed for Gram-positive anaerobes, including Bifidobacteria, Eggerthella, Finegoldia, and Peptostreptococcus (MIC90 >512, >512, 64, and 64 μg/mL) compared with VAN (MIC90 1, 4, 0.5, and 0.5 μg/mL). Bacteroides fragilis MIC90 for RDZ and VAN were >512 and 64 µg/mL, respectively. These in vitro data correlate closely with human microbiome profiles. RDZ reduced C. difficile to below detection with other reductions in abundancy observed in only 2 families from the Clostridia. VAN at EOT resulted in significant losses, often below detection, in 4 Firmicutes families, Actinobacteria, and Bacteroidetes and a 25-fold increase in Proteobacteria abundance. The preservation of the microbiome by RDZ likely accounted for reduced rCDI compared with VAN with RDZ shown to be superior on SCR to VAN with rates of 66.7% and 42.4%, respectively (pre-specified 90% CI 3.1, 39.1).ConclusionThese data demonstrate strong translation of in vitro spectrum to human gut microbiome preservation during therapy and support further clinical development of RDZ.Disclosures R. Vickers, Summit Therapeutics: Employee, Salary and Stock options. E. J. C. Goldstein, Summit Therapeutics: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient. D. Citron, Summit Therapeutics: Grant Investigator, Research grant. D. Snydman, Summit Therapeutics: Grant Investigator, Grant recipient. C. M. Thorpe, Summit Therapeutics: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient. A. V. Kane, Summit Therapeutics: Grant Investigator, Grant recipient.

PanGFR-HM: A Dynamic Web Resource for Pan-Genomic and Functional Profiling of Human Microbiome With Comparative Features.

The conglomerate of microorganisms inhabiting various body-sites of human, known as the human microbiome, is one of the key determinants of human health and disease. Comprehensive pan-genomic and functional analysis approach for human microbiome components can enrich our understanding about impact of microbiome on human health. By utilizing this approach we developed PanGFR-HM (http://www.bioinfo.iicb.res.in/pangfr-hm/) – a novel dynamic web-resource that integrates genomic and functional characteristics of 1293 complete microbial genomes available from Human Microbiome Project. The resource allows users to explore genomic/functional diversity and genome-based phylogenetic relationships between human associated microbial genomes, not provided by any other resource. The key features implemented here include pan-genome and functional analysis of organisms based on taxonomy or body-site, and comparative analysis between groups of organisms. The first feature can also identify probable gene-loss events and significantly over/under represented KEGG/COG categories within pan-genome. The unique second feature can perform comparative genomic, functional and pathways analysis between 4 groups of microbes. The dynamic nature of this resource enables users to define parameters for orthologous clustering and to select any set of organisms for analysis. As an application for comparative feature of PanGFR-HM, we performed a comparative analysis with 67 Lactobacillus genomes isolated from human gut, oral cavity and urogenital tract, and therefore characterized the body-site specific genes, enzymes and pathways. Altogether, PanGFR-HM, being unique in its content and functionality, is expected to provide a platform for microbiome-based comparative functional and evolutionary genomics.