Daptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids

ABSTRACT Treatment of multidrug-resistant enterococci has become a challenging clinical problem in hospitals around the world due to the lack of reliable therapeutic options. Daptomycin (DAP), a cell membrane-targeting cationic antimicrobial lipopeptide, is the only antibiotic with in vitro bacteric...

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Autores principales:	Truc T. Tran, Diana Panesso, Nagendra N. Mishra, Eugenia Mileykovskaya, Ziqianq Guan, Jose M. Munita, Jinnethe Reyes, Lorena Diaz, George M. Weinstock, Barbara E. Murray, Yousif Shamoo, William Dowhan, Arnold S. Bayer, Cesar A. Arias
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/21935d38afa0486c929d749b8d19f88c
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spelling	oai:doaj.org-article:21935d38afa0486c929d749b8d19f88c2021-11-15T15:43:08ZDaptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids10.1128/mBio.00281-132150-7511https://doaj.org/article/21935d38afa0486c929d749b8d19f88c2013-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00281-13https://doaj.org/toc/2150-7511ABSTRACT Treatment of multidrug-resistant enterococci has become a challenging clinical problem in hospitals around the world due to the lack of reliable therapeutic options. Daptomycin (DAP), a cell membrane-targeting cationic antimicrobial lipopeptide, is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant enterococci (VRE). However, the clinical use of DAP against VRE is threatened by emergence of resistance during therapy, but the mechanisms leading to DAP resistance are not fully understood. The mechanism of action of DAP involves interactions with the cell membrane in a calcium-dependent manner, mainly at the level of the bacterial septum. Previously, we demonstrated that development of DAP resistance in vancomycin-resistant Enterococcus faecalis is associated with mutations in genes encoding proteins with two main functions, (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase). In this work, we show that these VRE can resist DAP-elicited cell membrane damage by diverting the antibiotic away from its principal target (division septum) to other distinct cell membrane regions. DAP septal diversion by DAP-resistant E. faecalis is mediated by initial redistribution of cell membrane cardiolipin-rich microdomains associated with a single amino acid deletion within the transmembrane protein LiaF (a member of a three-component regulatory system [LiaFSR] involved in cell envelope homeostasis). Full expression of DAP resistance requires additional mutations in enzymes (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase) that alter cell membrane phospholipid content. Our findings describe a novel mechanism of bacterial resistance to cationic antimicrobial peptides. IMPORTANCE The emergence of antibiotic resistance in bacterial pathogens is a threat to public health. Understanding the mechanisms of resistance is of crucial importance to develop new strategies to combat multidrug-resistant microorganisms. Vancomycin-resistant enterococci (VRE) are one of the most recalcitrant hospital-associated pathogens against which new therapies are urgently needed. Daptomycin (DAP) is a calcium-decorated antimicrobial lipopeptide whose target is the bacterial cell membrane. A current paradigm suggests that Gram-positive bacteria become resistant to cationic antimicrobial peptides via an electrostatic repulsion of the antibiotic molecule from a more positively charged cell surface. In this work, we provide evidence that VRE use a novel strategy to avoid DAP-elicited killing. Instead of “repelling” the antibiotic from the cell surface, VRE diverts the antibiotic molecule from the septum and “traps” it in distinct membrane regions. We provide genetic and biochemical bases responsible for the mechanism of resistance and disclose new targets for potential antimicrobial development.Truc T. TranDiana PanessoNagendra N. MishraEugenia MileykovskayaZiqianq GuanJose M. MunitaJinnethe ReyesLorena DiazGeorge M. WeinstockBarbara E. MurrayYousif ShamooWilliam DowhanArnold S. BayerCesar A. AriasAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 4 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Truc T. Tran Diana Panesso Nagendra N. Mishra Eugenia Mileykovskaya Ziqianq Guan Jose M. Munita Jinnethe Reyes Lorena Diaz George M. Weinstock Barbara E. Murray Yousif Shamoo William Dowhan Arnold S. Bayer Cesar A. Arias Daptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids
description	ABSTRACT Treatment of multidrug-resistant enterococci has become a challenging clinical problem in hospitals around the world due to the lack of reliable therapeutic options. Daptomycin (DAP), a cell membrane-targeting cationic antimicrobial lipopeptide, is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant enterococci (VRE). However, the clinical use of DAP against VRE is threatened by emergence of resistance during therapy, but the mechanisms leading to DAP resistance are not fully understood. The mechanism of action of DAP involves interactions with the cell membrane in a calcium-dependent manner, mainly at the level of the bacterial septum. Previously, we demonstrated that development of DAP resistance in vancomycin-resistant Enterococcus faecalis is associated with mutations in genes encoding proteins with two main functions, (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase). In this work, we show that these VRE can resist DAP-elicited cell membrane damage by diverting the antibiotic away from its principal target (division septum) to other distinct cell membrane regions. DAP septal diversion by DAP-resistant E. faecalis is mediated by initial redistribution of cell membrane cardiolipin-rich microdomains associated with a single amino acid deletion within the transmembrane protein LiaF (a member of a three-component regulatory system [LiaFSR] involved in cell envelope homeostasis). Full expression of DAP resistance requires additional mutations in enzymes (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase) that alter cell membrane phospholipid content. Our findings describe a novel mechanism of bacterial resistance to cationic antimicrobial peptides. IMPORTANCE The emergence of antibiotic resistance in bacterial pathogens is a threat to public health. Understanding the mechanisms of resistance is of crucial importance to develop new strategies to combat multidrug-resistant microorganisms. Vancomycin-resistant enterococci (VRE) are one of the most recalcitrant hospital-associated pathogens against which new therapies are urgently needed. Daptomycin (DAP) is a calcium-decorated antimicrobial lipopeptide whose target is the bacterial cell membrane. A current paradigm suggests that Gram-positive bacteria become resistant to cationic antimicrobial peptides via an electrostatic repulsion of the antibiotic molecule from a more positively charged cell surface. In this work, we provide evidence that VRE use a novel strategy to avoid DAP-elicited killing. Instead of “repelling” the antibiotic from the cell surface, VRE diverts the antibiotic molecule from the septum and “traps” it in distinct membrane regions. We provide genetic and biochemical bases responsible for the mechanism of resistance and disclose new targets for potential antimicrobial development.
format	article
author	Truc T. Tran Diana Panesso Nagendra N. Mishra Eugenia Mileykovskaya Ziqianq Guan Jose M. Munita Jinnethe Reyes Lorena Diaz George M. Weinstock Barbara E. Murray Yousif Shamoo William Dowhan Arnold S. Bayer Cesar A. Arias
author_facet	Truc T. Tran Diana Panesso Nagendra N. Mishra Eugenia Mileykovskaya Ziqianq Guan Jose M. Munita Jinnethe Reyes Lorena Diaz George M. Weinstock Barbara E. Murray Yousif Shamoo William Dowhan Arnold S. Bayer Cesar A. Arias
author_sort	Truc T. Tran
title	Daptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids
title_short	Daptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids
title_full	Daptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids
title_fullStr	Daptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids
title_full_unstemmed	Daptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids
title_sort	daptomycin-resistant <named-content content-type="genus-species">enterococcus faecalis</named-content> diverts the antibiotic molecule from the division septum and remodels cell membrane phospholipids
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/21935d38afa0486c929d749b8d19f88c
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Daptomycin-Resistant <named-content content-type="genus-species">Enterococcus faecalis</named-content> Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids

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