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...

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Autores principales:	Nicholas K. Goldner, Christopher Bulow, Kevin Cho, Meghan Wallace, Fong-Fu Hsu, Gary J. Patti, Carey-Ann Burnham, Paul Schlesinger, Gautam Dantas
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Corynebacterium antimicrobial resistance artificial liposomes daptomycin genomics lipidomics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/55376da390494f18bac0b4a834f05155
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spelling	oai:doaj.org-article:55376da390494f18bac0b4a834f051552021-11-15T15:25:50ZMechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic>10.1128/mSphereDirect.00371-182379-5042https://doaj.org/article/55376da390494f18bac0b4a834f051552018-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphereDirect.00371-18https://doaj.org/toc/2379-5042ABSTRACT 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.Nicholas K. GoldnerChristopher BulowKevin ChoMeghan WallaceFong-Fu HsuGary J. PattiCarey-Ann BurnhamPaul SchlesingerGautam DantasAmerican Society for MicrobiologyarticleCorynebacteriumantimicrobial resistanceartificial liposomesdaptomycingenomicslipidomicsMicrobiologyQR1-502ENmSphere, Vol 3, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Corynebacterium antimicrobial resistance artificial liposomes daptomycin genomics lipidomics Microbiology QR1-502
spellingShingle	Corynebacterium antimicrobial resistance artificial liposomes daptomycin genomics lipidomics Microbiology QR1-502 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>
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.
format	article
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
title	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_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_sort	mechanism of high-level daptomycin resistance in <italic toggle="yes">corynebacterium striatum</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/55376da390494f18bac0b4a834f05155
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Mechanism of High-Level Daptomycin Resistance in <italic toggle="yes">Corynebacterium striatum</italic>

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