Daptomycin Resistance in Enterococci is Associated with Distinct Alterations of Cell Membrane Phospholipid Content

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Sep 7

PMID 22952824

Citations 78

Authors

Nagendra N Mishra

Arnold S Bayer

Truc T Tran

Yousif Shamoo

Eugenia Mileykovskaya

William Dowhan

Ziqiang Guan

Cesar A Arias

Affiliations

Soon will be listed here.

Abstract

Background: The lipopeptide antibiotic, daptomycin (DAP) interacts with the bacterial cell membrane (CM). Development of DAP resistance during therapy in a clinical strain of Enterococcus faecalis was associated with mutations in genes encoding enzymes involved in cell envelope homeostasis and phospholipid metabolism. Here we characterized changes in CM phospholipid profiles associated with development of DAP resistance in clinical enterococcal strains.

Methodology: Using two clinical strain-pairs of DAP-susceptible and DAP-resistant E. faecalis (S613 vs. R712) and E. faecium (S447 vs. R446) recovered before and after DAP therapy, we compared four distinct CM profiles: phospholipid content, fatty acid composition, membrane fluidity and capacity to be permeabilized and/or depolarized by DAP. Additionally, we characterized the cell envelope of the E. faecium strain-pair by transmission electron microscopy and determined the relative cell surface charge of both strain-pairs.

Principal Findings: Both E. faecalis and E. faecium mainly contained four major CM PLs: phosphatidylglycerol (PG), cardiolipin, lysyl-phosphatidylglycerol (L-PG) and glycerolphospho-diglycodiacylglycerol (GP-DGDAG). In addition, E. faecalis CMs (but not E. faecium) also contained: i) phosphatidic acid; and ii) two other unknown species of amino-containing PLs. Development of DAP resistance in both enterococcal species was associated with a significant decrease in CM fluidity and PG content, with a concomitant increase in GP-DGDAG. The strain-pairs did not differ in their outer CM translocation (flipping) of amino-containing PLs. Fatty acid content did not change in the E. faecalis strain-pair, whereas a significant decrease in unsaturated fatty acids was observed in the DAP-resistant E. faecium isolate R446 (vs S447). Resistance to DAP in E. faecium was associated with distinct structural alterations of the cell envelope and cell wall thickening, as well as a decreased ability of DAP to depolarize and permeabilize the CM.

Conclusion: Distinct alterations in PL content and fatty acid composition are associated with development of enterococcal DAP resistance.

Citing Articles

Molecular basis of cell membrane adaptation in daptomycin-resistant Enterococcus faecalis.

Nguyen A, Tran T, Panesso D, Hood K, Polamraju V, Zhang R JCI Insight. 2024; 9(22).

PMID: 39405116 PMC: 11601895. DOI: 10.1172/jci.insight.173836.

Overexpression of diglucosyldiacylglycerol synthase leads to daptomycin resistance in .

Yamamoto R, Ishikawa K, Miyoshi Y, Furuta K, Miyoshi S, Kaito C J Bacteriol. 2024; 206(10):e0030724.

PMID: 39235960 PMC: 11500525. DOI: 10.1128/jb.00307-24.

Current insights into the effects of cationic biocides exposure on spp.

Pereira A, Antunes P, Peixe L, Freitas A, Novais C Front Microbiol. 2024; 15:1392018.

PMID: 39006755 PMC: 11242571. DOI: 10.3389/fmicb.2024.1392018.

Antibacterial activity of a short de novo designed peptide against fish bacterial pathogens.

Bhat R, Khangembam V, Pant V, Tandel R, Pandey P, Thakuria D Amino Acids. 2024; 56(1):28.

PMID: 38578302 PMC: 10997546. DOI: 10.1007/s00726-024-03388-4.

The intricate link between membrane lipid structure and composition and membrane structural properties in bacterial membranes.

Lee T, Charchar P, Separovic F, Reid G, Yarovsky I, Aguilar M Chem Sci. 2024; 15(10):3408-3427.

PMID: 38455013 PMC: 10915831. DOI: 10.1039/d3sc04523d.

References

Peschel A, Otto M, JACK R, Kalbacher H, Jung G, Gotz F . Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J Biol Chem. 1999; 274(13):8405-10. DOI: 10.1074/jbc.274.13.8405. View

Dowhan W . Molecular basis for membrane phospholipid diversity: why are there so many lipids?. Annu Rev Biochem. 1997; 66:199-232. DOI: 10.1146/annurev.biochem.66.1.199. View

Zhang W, Campbell H, King S, Dowhan W . Phospholipids as determinants of membrane protein topology. Phosphatidylethanolamine is required for the proper topological organization of the gamma-aminobutyric acid permease (GabP) of Escherichia coli. J Biol Chem. 2005; 280(28):26032-8. DOI: 10.1074/jbc.M504929200. View

Ambron R, Pieringer R . The metabolism of glyceride glycolipids. V. Identification of the membrane lipid formed from diglucosyl diglyceride in Streptococcus faecalis ATCC 9790 as an acylated derivative of glyceryl phosphoryl diglucosyl glycerol. J Biol Chem. 1971; 246(13):4216-25. View

Sakayori Y, Muramatsu M, Hanada S, Kamagata Y, Kawamoto S, Shima J . Characterization of Enterococcus faecium mutants resistant to mundticin KS, a class IIa bacteriocin. Microbiology (Reading). 2003; 149(Pt 10):2901-2908. DOI: 10.1099/mic.0.26435-0. View

Arias C, Panesso D, McGrath D, Qin X, Mojica M, Miller C . Genetic basis for in vivo daptomycin resistance in enterococci. N Engl J Med. 2011; 365(10):892-900. PMC: 3205971. DOI: 10.1056/NEJMoa1011138. View

Fischer W, Landgraf H . Glycerophosphoryl phosphatidyl kojibiosyl diacylglycerol, a novel phosphoglucolipid from Streptococcus faecalis. Biochim Biophys Acta. 1975; 380(2):227-44. DOI: 10.1016/0005-2760(75)90009-0. View

dos Santos Mota J, den Kamp J, Verheij H, Van Deenen L . Phospholipids of Streptococcus faecalis. J Bacteriol. 1970; 104(2):611-9. PMC: 285035. DOI: 10.1128/jb.104.2.611-619.1970. View

Glickman M, Cox J, Jacobs Jr W . A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell. 2000; 5(4):717-27. DOI: 10.1016/s1097-2765(00)80250-6. View

10.

Jones T, Yeaman M, Sakoulas G, Yang S, Proctor R, Sahl H . Failures in clinical treatment of Staphylococcus aureus Infection with daptomycin are associated with alterations in surface charge, membrane phospholipid asymmetry, and drug binding. Antimicrob Agents Chemother. 2007; 52(1):269-78. PMC: 2223911. DOI: 10.1128/AAC.00719-07. View

11.

Green M, Anasetti C, Sandin R, Rolfe N, Greene J . Development of daptomycin resistance in a bone marrow transplant patient with vancomycin-resistant Enterococcus durans. J Oncol Pharm Pract. 2006; 12(3):179-81. DOI: 10.1177/1078155206069165. View

12.

Fowler Jr V, Boucher H, Corey G, Abrutyn E, Karchmer A, Rupp M . Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006; 355(7):653-65. DOI: 10.1056/NEJMoa053783. View

13.

Twilla J, Finch C, Usery J, Gelfand M, Hudson J, Broyles J . Vancomycin-resistant Enterococcus bacteremia: an evaluation of treatment with linezolid or daptomycin. J Hosp Med. 2011; 7(3):243-8. DOI: 10.1002/jhm.994. View

14.

Carson D, Pieringer R . Effect of cerulenin on cellular autolytic activity and lipid metabolism during inhibition of protein synthesis in Streptococcus faecalis. J Bacteriol. 1981; 146(2):590-604. PMC: 217002. DOI: 10.1128/jb.146.2.590-604.1981. View

15.

Zhang Y, Rock C . Membrane lipid homeostasis in bacteria. Nat Rev Microbiol. 2008; 6(3):222-33. DOI: 10.1038/nrmicro1839. View

16.

Mehta S, Cuirolo A, Plata K, Riosa S, Silverman J, Rubio A . VraSR two-component regulatory system contributes to mprF-mediated decreased susceptibility to daptomycin in in vivo-selected clinical strains of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011; 56(1):92-102. PMC: 3256076. DOI: 10.1128/AAC.00432-10. View

17.

Bertsche U, Weidenmaier C, Kuehner D, Yang S, Baur S, Wanner S . Correlation of daptomycin resistance in a clinical Staphylococcus aureus strain with increased cell wall teichoic acid production and D-alanylation. Antimicrob Agents Chemother. 2011; 55(8):3922-8. PMC: 3147621. DOI: 10.1128/AAC.01226-10. View

18.

Ernst C, Staubitz P, Mishra N, Yang S, Hornig G, Kalbacher H . The bacterial defensin resistance protein MprF consists of separable domains for lipid lysinylation and antimicrobial peptide repulsion. PLoS Pathog. 2009; 5(11):e1000660. PMC: 2774229. DOI: 10.1371/journal.ppat.1000660. View

19.

Ganfield M, Pieringer R . The biosynthesis of nascent membrane lipoteichoic acid of Streptococcus faecium (S. faecalis ATCC 9790) from phosphatidylkojibiosyl diacylglycerol and phosphatidylglycerol. J Biol Chem. 1980; 255(11):5164-9. View

20.

Dixit B, Gupta C . Role of the actin cytoskeleton in regulating the outer phosphatidylethanolamine levels in yeast plasma membrane. Eur J Biochem. 1998; 254(1):202-6. DOI: 10.1046/j.1432-1327.1998.2540202.x. View