Washington University in St. Louis

The Patti Lab
Metabolomics to elucidate novel biochemical mechanisms of disease
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Mechanism of High-Level Daptomycin Resistance in Corynebacterium striatum

Goldner NK, Bulow C, Cho K, Wallace M, Hsu F-F, Patti GJ, Burnham C-A, Schlesinger P, and Dantas G
Mechanism of High-Level Daptomycin Resistance in Corynebacterium striatum
mSphere, 3:e00371-18, 2018

Daptomycin, a last-line-of-defense antibiotic for treating Gram-positive infections, is experiencing clinical failure against important infectious agents, includ- ing Corynebacterium striatum. The recent transition of daptomycin to generic status is projected to dramatically increase availability, use, and clinical failure. Here we confirm the genetic mechanism of high-level daptomycin resistance (HLDR; MIC > 256 µg/ml) in C. striatum, which evolved within a patient during daptomycin ther- apy, a phenotype recapitulated in vitro. In all 8 independent cases tested, loss-of- function mutations in phosphatidylglycerol synthase (pgsA2) were necessary and suf- ficient for high-level daptomycin resistance. Through lipidomic and biochemical analysis, we demonstrate that daptomycin’s activity is dependent on the membrane phosphatidylglycerol (PG) concentration. Until now, the verification of PG as the in vivo target of daptomycin has proven difficult since tested cell model systems were not viable without membrane PG. C. striatum becomes daptomycin resistant at a high level by removing PG from the membrane and changing the membrane com- position to maintain viability. This work demonstrates that loss-of-function mutation in pgsA2 and the loss of membrane PG are necessary and sufficient to produce high- level resistance to daptomycin in C. striatum.

Washington University, Departments of Chemistry, Genetics, and Medicine. Saint Louis, Missouri 63110 USA