Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic>
ABSTRACT Daptomycin, a last-line-of-defense antibiotic for treating Gram-positive infections, is experiencing clinical failure against important infectious agents, including Corynebacterium striatum. The recent transition of daptomycin to generic status is projected to dramatically increase availabi...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2018-08-01
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| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSphereDirect.00371-18 |
| _version_ | 1819041461306392576 |
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| author | Nicholas K. Goldner Christopher Bulow Kevin Cho Meghan Wallace Fong-Fu Hsu Gary J. Patti Carey-Ann Burnham Paul Schlesinger Gautam Dantas |
| author_facet | Nicholas K. Goldner Christopher Bulow Kevin Cho Meghan Wallace Fong-Fu Hsu Gary J. Patti Carey-Ann Burnham Paul Schlesinger Gautam Dantas |
| author_sort | Nicholas K. Goldner |
| collection | DOAJ |
| description | ABSTRACT Daptomycin, a last-line-of-defense antibiotic for treating Gram-positive infections, is experiencing clinical failure against important infectious agents, including 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 therapy, a phenotype recapitulated in vitro. In all 8 independent cases tested, loss-of-function mutations in phosphatidylglycerol synthase (pgsA2) were necessary and sufficient 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 composition 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. IMPORTANCE Antimicrobial resistance threatens the efficacy of antimicrobial treatment options, including last-line-of-defense drugs. Understanding how this resistance develops can help direct antimicrobial stewardship efforts and is critical to designing the next generation of antimicrobial therapies. Here we determine how Corynebacterium striatum, a skin commensal and opportunistic pathogen, evolved high-level resistance to a drug of last resort, daptomycin. Through a single mutation, this pathogen was able to remove the daptomycin’s target, phosphatidylglycerol (PG), from the membrane and evade daptomycin’s bactericidal activity. We found that additional compensatory changes were not necessary to support the removal of PG and replacement with phosphatidylinositol (PI). The ease with which C. striatum evolved high-level resistance is cause for alarm and highlights the importance of screening new antimicrobials against a wide range of clinical pathogens which may harbor unique capacities for resistance evolution. |
| first_indexed | 2024-12-21T09:25:22Z |
| format | Article |
| id | doaj.art-55376da390494f18bac0b4a834f05155 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-12-21T09:25:22Z |
| publishDate | 2018-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-55376da390494f18bac0b4a834f051552022-12-21T19:08:54ZengAmerican Society for MicrobiologymSphere2379-50422018-08-013410.1128/mSphereDirect.00371-18Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic>Nicholas K. Goldner0Christopher Bulow1Kevin Cho2Meghan Wallace3Fong-Fu Hsu4Gary J. Patti5Carey-Ann Burnham6Paul Schlesinger7Gautam Dantas8Edison Family Center for Genome Sciences & Systems Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USAEdison Family Center for Genome Sciences & Systems Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USADepartment of Chemistry, Washington University in St. Louis, St. Louis, Missouri, USADepartment of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri, USADivision of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Chemistry, Washington University in St. Louis, St. Louis, Missouri, USADepartment of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, Missouri, USAEdison Family Center for Genome Sciences & Systems Biology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USAABSTRACT Daptomycin, a last-line-of-defense antibiotic for treating Gram-positive infections, is experiencing clinical failure against important infectious agents, including 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 therapy, a phenotype recapitulated in vitro. In all 8 independent cases tested, loss-of-function mutations in phosphatidylglycerol synthase (pgsA2) were necessary and sufficient 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 composition 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. IMPORTANCE Antimicrobial resistance threatens the efficacy of antimicrobial treatment options, including last-line-of-defense drugs. Understanding how this resistance develops can help direct antimicrobial stewardship efforts and is critical to designing the next generation of antimicrobial therapies. Here we determine how Corynebacterium striatum, a skin commensal and opportunistic pathogen, evolved high-level resistance to a drug of last resort, daptomycin. Through a single mutation, this pathogen was able to remove the daptomycin’s target, phosphatidylglycerol (PG), from the membrane and evade daptomycin’s bactericidal activity. We found that additional compensatory changes were not necessary to support the removal of PG and replacement with phosphatidylinositol (PI). The ease with which C. striatum evolved high-level resistance is cause for alarm and highlights the importance of screening new antimicrobials against a wide range of clinical pathogens which may harbor unique capacities for resistance evolution.https://journals.asm.org/doi/10.1128/mSphereDirect.00371-18Corynebacteriumantimicrobial resistanceartificial liposomesdaptomycingenomicslipidomics |
| spellingShingle | Nicholas K. Goldner Christopher Bulow Kevin Cho Meghan Wallace Fong-Fu Hsu Gary J. Patti Carey-Ann Burnham Paul Schlesinger Gautam Dantas Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic> mSphere Corynebacterium antimicrobial resistance artificial liposomes daptomycin genomics lipidomics |
| title | Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic> |
| title_full | Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic> |
| title_fullStr | Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic> |
| title_full_unstemmed | Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic> |
| title_short | Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic> |
| title_sort | mechanism of high level daptomycin resistance in italic toggle yes corynebacterium striatum italic |
| topic | Corynebacterium antimicrobial resistance artificial liposomes daptomycin genomics lipidomics |
| url | https://journals.asm.org/doi/10.1128/mSphereDirect.00371-18 |
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