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Background DAP is used off-label for treatment of severe enterococcal infections. DAP resistance (R) in E. faecium has been associated with changes in LiaFSR, a three-component regulatory system that controls the cell envelope stress response to antibiotics. In particular, substitutions in LiaS (T120A) and LiaR (W73C) seem to predispose to development of DAP-R during therapy, without increasing the DAP MIC above the clinical breakpoint. Using a PK/PD model of simulated endocardial vegetations, we evaluated the genomic pathways for DAP-R under different DAP dose schemes. Methods A DAP-susceptible E. faecium (HOU503; MIC 3 mg/ml) harboring the above LiaSR substitutions, was subjected to simulated human doses of 6, 8, and 10 mg/kg/d in the model for 14 days using a starting inoculum of 109 CFU/ml. Sixteen DAP-R isolates were recovered from the SEV model: five isolates from 6 mg/kg (D6 isolates from days 2 to 14); five isolates from 8 mg/kg (D8 isolates from days 2 to 8); and six isolates from 10 mg/kg (D10 isolates from days 1 to 14) which were subjected to whole genome sequencing. Reads from each sequenced isolate were mapped against the HOU503 genome for SNP analyses. Variant calling was done with GATK, SamTools, and the low-frequency variant detector from CLC Genomics Workbench 8.5. Variants detected by the three callers were selected and annotated with SnpEff; then compared among the different groups of isolates accordingly to the DAP doses that were exposed. Results We detected a total of 16 proteins exhibiting substitutions consistently in all the DAP-R sequenced isolates; including mobile genetic elements (9), hypothetical proteins (2), a bacteriocin, a cysteine desulfurase, a N-acetylglucosamine-specific PTS system, a N-acetylmannosamine-6-phosphate 2-epimerase and a MurR/RpiR, which is a transcriptional regulator that represses the operon MurPQ involved in the uptake and degradation of N-acetylmuramic acid. Notably, mutations in cardiolipin synthase were present only in isolates recovered under D8 dose. The LiaRS substitutions remained in all isolates. Conclusion Using a humanized SEV PK/PD model and SNP-based analyses, we were able to uncover possible novel genetic pathways associated with the development DAP-R via the LiaFSR system in enterococci. Disclosures M. J. Rybak, Allergen: Scientific Advisor, Consulting fee

Genomic Pathways Associated with Daptomycin (DAP) Resistance in DAP-Susceptible Enterococcus faecium Harboring Substitutions in LiaFSR