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Antimicrobial Agents and Chemotherapy, October 2000, p. 2845-2847, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The D-Alanine Residues of
Staphylococcus aureus Teichoic Acids Alter the
Susceptibility to Vancomycin and the Activity of Autolytic
Enzymes
Andreas
Peschel,*
Cuong
Vuong,
Michael
Otto, and
Friedrich
Götz
Microbial Genetics, University of
Tübingen, 72076 Tübingen, Germany
Received 29 November 1999/Returned for modification 18 March
2000/Accepted 15 June 2000
 |
ABSTRACT |
Recently, Staphylococcus aureus strains with
intermediate resistance to vancomycin, the antibiotic of last resort,
have been described. Multiple changes in peptidoglycan turnover and
structure contribute to the resistance phenotype. Here, we describe
that structural changes of teichoic acids in the cell envelope have a
considerable influence on the susceptibility to vancomycin and other
glycopeptides. S. aureus cells lacking
D-alanine esters in teichoic acids exhibited an at least
threefold-increased sensitivity to glycopeptide antibiotics.
Furthermore, the autolytic activity of the D-alanine mutant
was reduced compared to the wild-type, and the mutant was more
susceptible to the staphylolytic enzyme lysostaphin. Vancomycin
inhibited autolysis at very high concentrations but neither in the
wild-type nor in the mutant was the autolytic activity influenced in
the range of the MIC. Mutant cells had a considerably higher capacity
to bind vancomycin.
| |
TEXT |
Many important antimicrobial agents
such as 
-lactam and glycopeptide antibiotics attack the components
of bacterial cell wall turnover and synthesis. However, the increasing
prevalence of strains of the major human pathogen Staphylococcus
aureus with resistance to almost all available antibiotics has
become a threatening problem (10). Recently, reduced
susceptibilities to the glycopeptides vancomycin and teicoplanin, which
represent the last options for the treatment of multidrug-resistant
staphylococci have been reported among clinical S. aureus
isolates (8, 17). While the glycopeptide resistance systems
of enterococci are well characterized (1, 22), the
mechanisms influencing the susceptibility to vancomycin and teicoplanin
in staphylococci are less understood. Multiple changes in the cell wall
involving the rate of peptidoglycan precursor synthesis, cell wall
thickness, peptidoglycan cross-linking, and amount of muropeptides with
deamidated glutamine residues have been reported to influence the
sensitivity of S. aureus to glycopeptide antibiotics
(6, 7). In vancomycin- and teicoplanin-resistant laboratory
mutants, a dramatic increase of monomeric muropeptides containing the
D-alanyl-D-alanine dipeptide, the binding
motive of glycopeptide antibiotics, has been observed (18,
19). The binding sites in mature peptidoglycan compete with the
D-alanyl-D-alanine dipeptides of lipid-bound
murein precursors, the vancomycin target sites, for binding of
vancomycin (18). Not only does vancomycin block
peptidoglycan synthesis, but it also has the capacity to inhibit
autolysins of the cell wall (18).
Besides peptidoglycan, the S. aureus cell wall contains
polymers of alternating phosphate and alditol groups called teichoic acids (3). These polymer chains are either covalently
connected to the peptidoglycan (wall teichoic acids) (15) or
to membrane glycolipids (lipoteichoic acids) (4). The highly
charged teichoic acids are involved in the control of autolysin
activity (3). We have recently described an S. aureus mutant lacking D-alanine in the teichoic acids
since the dltABCD operon responsible for the
D-alanine transfer into teichoic acids was disrupted
(14). This pathway is not involved in the synthesis of
murein precursors. The mutant was sensitive to cationic pore-forming
antimicrobial peptides such as nisin from Lactococcus
lactis, 
-defensins from the human immune system, and related
peptides. Here, we report that the absence of D-alanine
esters in teichoic acids has a profound influence on the susceptibility
to glycopeptide antibiotics and on autolysin activity.
Activity of antibiotics against the dlt mutant and the
parental strain.
We compared the MICs of various antibiotics for
S. aureus Sa113 wild-type, dlt mutant, and
dlt mutant complemented with plasmid pRBdlt1. Construction
of the mutant and plasmid has been described recently (14).
Serial threefold dilutions of the various antibiotics in LB broth (1%
tryptone, 0.5% yeast extract, 0.5% NaCl [pH 7.0]) were inoculated
with 1/100 volume of precultures which had been adjusted to the same
cell density. Tubes with 400-µl aliquots were shaken at 37°C, and
after 8 h the A600 was determined. The values in Table 1 represent the
antibiotic concentrations causing a 75% reduction of growth as
calculated by interpolation. The assay was carried out at least two
times with several identical samples, yielding very reproducible
results. While the mutant was only slightly more sensitive (less than
twofold) than the wild type to methicillin, cefazolin, erythromycin,
and tetracycline, a considerable increase of the susceptibility (more
than threefold) to the glycopeptide antibiotics vancomycin,
teicoplanin, and balhimycin was observed. Complementation of the mutant
with plasmid pRBdlt1 bearing the intact dltABCD operon
restored the tolerance to glycopeptide antibiotics to wild-type levels.
Balhimycin belongs to the vancomycin class of glycopeptides. It is not
approved for medical use yet (11, 13).
Autolytic properties and lysostaphin-induced lysis.
The
D-alanine esters introduce positively charged amino groups
into the otherwise negatively charged teichoic acids. In Bacillus subtilis, the absence of D-alanine from the polymers
has been reported to cause an alteration of the activity of autolytic
enzymes, which are considered to bind to teichoic acids by ionic
interactions (21). Since vancomycin has been shown to
inhibit the autolytic activity of S. aureus strains at high
concentrations (18), we compared the autolytic properties of
the parental and the mutant strain and a possible impact of any changes
on the sensitivity to vancomycin.
Cell wall-lytic enzymes were isolated from wild-type and dlt
mutant bacteria and visualized by zymographic analysis as described elsewhere (12, 16). Briefly, autolysins were isolated from bacteria grown for 12 h in BM broth (LB broth supplemented with 0.1% glucose and 0.1% K2HPO4) by boiling the
cells with 1% sodium dodecyl sulfate (SDS) and separated by
Tricine-SDS-polyacrylamide gel electrophoresis with gels containing
heat-inactivated S. aureus dlt mutant cells (2 mg/ml).
Autolytic enzyme activities (clearing zones) were visualized by
staining the gels with methylene blue. The autolysin patterns of the
two strains were very similar (Fig. 1A).
However, the clearing zones from the mutant were much smaller than
those of the wild type, suggesting that autolysins were less efficiently detached from the mutant cell walls. No differences were
observed in the autolysin patterns of the supernatants (data not
shown).
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FIG. 1.
Zymographic analysis (A) and spontaneous autolysis with
or without vancomycin (B) of S. aureus Sa113 wild type and
dltA mutant. (A) Equal amounts of cell wall-associated
proteins from S. aureus Sa113 wild type (lane 1) and from
the isogenic dltA mutant (lane 2) were applied to an
SDS-polyacrylamide gel containing heat-inactivated staphylococcal
cells. Molecular mass standards are indicated in kilodaltons. (B) Equal
amounts of cells were incubated without vancomycin (triangles), with 1 µg of vancomycin per ml (squares), or with 10 µg of vancomycin per
ml (circles). The values are given as percentages of the initial
A600.
|
|
In order to compare the spontaneous autolysis of wild-type S. aureus and the dlt mutant, the strains were grown until
late logarithmic phase in BM broth and washed twice with ice-cold
water. Equal amounts of bacteria were resuspended in sodium phosphate buffer (10 mM, pH 7.0), and the decrease of the
A600 was monitored during incubation at 30°C.
When no vancomycin was added, the dltA mutant exhibited a
reduced rate of autolysis (decrease of the cell density of 9.6%/h in
the mutant vs. 16%/h in the wild type in the linear parts of the
curves). Binding of the cationic autolysins to anionic teichoic acids
is regarded as a control mechanism that reduces their activity
(4); the stronger negative charge of the teichoic acids in
the mutant is thus likely to further increase the inhibition of
autolysins. Addition of 10 µg of vancomycin per ml caused a profound
inhibition of the spontaneous autolysis of both strains. However, a
vancomycin concentration of 1 µg/ml, which is close to the MIC had no
influence on the autolytic behavior of both the parental and mutant
strain. Therefore, it seems unlikely that vancomycin exerts its higher
activity against the mutant via increased inhibition of autolysis.
While the activity of endogenous cell wall-lytic enzymes seemed to be
reduced, the mutant was considerably more sensitive to the
glycyl-glycyl endopeptidase lysostaphin, a bacteriocin-like enzyme from
Staphylococcus simulans bv. staphylolyticus
(20) (Fig. 2). Its activity
was analyzed as described above for spontaneous autolysis except that
bacteria were washed and resuspended in phosphate-buffered saline (10 mM sodium phosphate buffer containing 130 mM NaCl; pH 7.4). This
observation suggests a role of anionic teichoic acids in the binding of
lysostaphin, which has previously been shown to bind to the cell wall
via its cationic C-terminal domain (2). Whether the polymers
represent the receptor molecules or have an indirect influence on
lysostaphin binding or activity remains to be analyzed.
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FIG. 2.
Lysostaphin-mediated lysis of wild type (solid symbols)
and dltA mutant (empty symbols). Equal amounts of cells were
incubated without (squares) or with (circles) lysostaphin (1 µg/ml).
The values are given as percentages of the initial
A600.
|
|
Vancomycin binding capacity.
Since the altered surface charge
of the mutant might influence the affinity for vancomycin, the
capacities of wild-type and mutant cells to bind vancomycin were
compared. Bacteria were grown in BM broth until late logarithmic phase,
washed twice in sodium phosphate buffer (100 mM, pH 7.0), and
resuspended in the same buffer to a final cell density of 2.5 × 1010/ml. After addition of vancomycin (1 µg/ml), the
cells were incubated for 20 min at ambient temperature and subsequently
removed by centrifugation. The amounts of unbound antibiotic were
determined by reversed-phase high-performance liquid chromatography
using a linear gradient of 0 to 100% acetonitrile in 0.1%
trifluoroacetic acid over 20 column volumes on a Spherisorb ODS2
column (Grom Analytik, Herrenberg, Germany). While in the supernatant
of the wild type (means ± standard deviations of three
independent determinations each) 54% ± 3% of the applied vancomycin
was detected, the supernatant of the mutant contained only 39% ± 7%,
which indicates that the binding capacity for vancomycin was increased
in the dlt mutant cells.
The phosphate contents of the cell walls, which provide a measure for
the teichoic acid content, were very similar in the wild type and
dlt mutant (means ± standard deviations of three independent determinations each: 0.69 ± 0.05 µmol/mg cell wall dry mass in the wild-type versus 0.65 ± 0.05 µmol/mg in the
dlt mutant). Cell walls were isolated and analyzed as
described recently (14) except that cells and cell walls
were washed and resuspended in water instead of sodium acetate buffer
and that extraction with SDS was repeated twice.
Concluding comments.
Our studies demonstrate that teichoic
acids have a considerable influence on the susceptibility to vancomycin
and related substances. This is consistent with two recently published
studies. (i) Sieradzki and Tomasz demonstrated that treatment of cell
walls with hydrofluoric acid, which removes the cell wall teichoic
acids, reduces the binding capacity of a resistant S. aureus
strain for vancomycin (18). (ii) Gutmann and coworkers
described that almost twice the normal amount of D-alanine
was attached to lipoteichoic acids of vancomycin-resistant
Enterococcus faecium strains (5). Since
glycopeptide antibiotics bind to
D-alanyl-D-alanine dipeptides, it is tempting
to speculate that the D-alanine substituents of teichoic
acids constitute alternative binding sites for the antibiotics. However, the dlt mutant bound more vancomycin than the
wild-type strain. Moreover, the teichoic acid D-alanine
esters contain positively charged amino groups while the terminal
D-alanine residues of murein peptides contain negatively
charged carboxyl groups. Therefore, a direct binding of vancomycin to
the D-alanine esters of teichoic acids is unlikely.
We found no indications for an autolysin-mediated inhibition of the
dlt mutant by vancomycin but an increased binding capacity of mutant cells for vancomycin, which may at least in part be responsible for the sensitivity of the mutant to glycopeptide antibiotics. Since the teichoic acid content and the degree of D-alanylation vary among S. aureus strains
(9), an increased amount of D-alanine esters may
contribute to vancomycin resistance in S. aureus.
| |
ACKNOWLEDGMENTS |
We thank Vera Augsburger for excellent technical assistance and
Stefan Pelzer for providing purified balhimycin.
This work was supported by a grant from the Deutsche
Forschungsgemeinschaft (GO 371/3-1).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Microbial
Genetics, University of Tübingen, Waldhäuser Str. 70/8,
72076 Tübingen, Germany. Phone: 49-7071-297-5938. Fax:
49-7071-29-5937. E-mail: andreas.peschel{at}uni-tuebingen.de.
| |
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Antimicrobial Agents and Chemotherapy, October 2000, p. 2845-2847, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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(2003). MprF-Mediated Lysinylation of Phospholipids in Staphylococcus aureus Leads to Protection against Oxygen-Independent Neutrophil Killing. Infect. Immun.
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Koprivnjak, T., Peschel, A., Gelb, M. H., Liang, N. S., Weiss, J. P.
(2002). Role of Charge Properties of Bacterial Envelope in Bactericidal Action of Human Group IIA Phospholipase A2 against Staphylococcus aureus. J. Biol. Chem.
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Ganz, T.
(2001). Fatal Attraction Evaded: How Pathogenic Bacteria Resist Cationic Polypeptides. J. Exp. Med.
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Peschel, A., Jack, R. W., Otto, M., Collins, L. V., Staubitz, P., Nicholson, G., Kalbacher, H., Nieuwenhuizen, W. F., Jung, G., Tarkowski, A., van Kessel, K. P.M., van Strijp, J. A.G.
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Gross, M., Cramton, S. E., Gotz, F., Peschel, A.
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Kiriukhin, M. Y., Neuhaus, F. C.
(2001). D-Alanylation of Lipoteichoic Acid: Role of the D-Alanyl Carrier Protein in Acylation. J. Bacteriol.
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Hille, M., Kies, S., Götz, F., Peschel, A.
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67: 1380-1383
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