|dc.contributor.author||Tran, Truc T.
Mishra, Nagendra N.
Munita, Jose M.
Weinstock, George M.
Murray, Barbara E.
Bayer, Arnold S.
Arias, Cesar A.
Tran, Truc T., Panesso, Diana, Mishra, Nagendra N., et al.. "Daptomycin-Resistant Enterococcus faecalis Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids." mBio, 4, no. 4 (2013) American Society for Microbiology: e00281-13. http://dx.doi.org/10.1128/mBio.00281-13.
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 calciumdependent
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.
American Society for Microbiology
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
Daptomycin-Resistant Enterococcus faecalis Diverts the Antibiotic Molecule from the Division Septum and Remodels Cell Membrane Phospholipids