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Antimicrobial Agents and Chemotherapy, January 2000, p. 169-172, Vol. 44, No. 1
Pharmazeutische Mikrobiologie, University of
Bonn, 53115 Bonn, Germany
Received 5 April 1999/Returned for modification 27 June
1999/Accepted 15 October 1999
Penicillin-binding proteins (PBPs) are involved in the regulation
of The production of After addition of a strong inducer like imipenem
NAcGlc-anhMurNAc-tripeptide
(N-acetylglucosaminyl-1,6-anhydro-N- acetylmuramyl-L-alanly-D-glutamyl-meso-diaminopimelicacid), NAcGlc-anhMurNAc-tetrapeptide (N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanly-D-glutamyl-meso-diaminopimelic-acid-D-alanine), and especially, NAcGlc-anhMurNAc-pentapeptide
(N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanly-D-glutamyl-meso- diaminopimelic-acid-D-alanyl-D-alanine)
accumulate in the periplasmatic space (5, 14).
Jacobs et al. (16) demonstrated that anhydromuramyl (aM)-tripeptide and aM-tetrapeptide convert the transcriptional factor
AmpR into an activator of The PBPs are cytoplasmic membrane enzymes involved in peptidoglycan
biosynthesis (8, 36, 37). Up to 12 PBPs have been identified
in Escherichia coli (1, 8, 10). They are able to
bind to
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Role of Penicillin-Binding Proteins in the
Initiation of the AmpC
-Lactamase Expression in
Enterobacter cloacae
ABSTRACT
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Abstract
Text
References
-lactamase expression by determining the level of
anhydromuramylpeptides in the periplasmatic space. It was hypothesized
that one or more PBPs act as a sensor in the -lactamase induction
pathway. We have performed induction studies with Escherichia
coli mutants lacking one to four PBPs with
DD-carboxypeptidase activity. Therefore, we conclude that a
strong -lactamase inducer must inhibit all DD-carboxypeptidases as well as the essential PBPs 1a, 1b,
and/or 2.
TEXT
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Abstract
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References
-lactamase is
the major mechanism of bacterial resistance to -lactam antibiotics.
These enzymes hydrolyze the -lactam ring and hence inactivate the
antibiotics before they reach their target, the penicillin-binding
proteins (PBPs) (8). In members of the family
Enterobacteriaceae the inducible production of the
chromosomal AmpC -lactamase is mediated by the genes
ampC, ampR, ampD, and
ampG (18-23) and is closely linked with
the recycling of the peptidoglycan (5, 11, 14-17,
40; D. Pfeifle, H. Dietz, E. Janas, I. Wiegand, and
B. B. Wiedemann, Abstr. 38th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. C-003, 1998). -Lactam antibiotics
differ markedly in their induction potentials. Imipenem and cefoxitin
are strong inducers, while aztreonam and ceftazidime are not
(5). As these two groups of -lactam antibiotics
differ in their affinities for the PBPs, it was hypothesized that one
or more PBPs act as a sensor in the -lactamase induction
pathway (5, 27, 30, 31, 35, 40; Pfeifle, 38th ICAAC).
-lactamase expression. We believe that the
aM-pentapeptide plays an important role in the induction process,
because we could demonstrate a clear correlation between the amount of
the aM-pentapeptide, the amount of the -lactamase, and the induction
capacity (5).
-lactam antibiotics covalently at a conserved active serine
residue because of their structural homology with the natural substrate
D-alanine-D-alanine for transpeptidation.
High-molecular-weight PBPs 1a, 1b, 2, and 3 are essential for growth
and survival of the bacterial cell. PBPs 1a and 1b are believed
to be dual transpeptidases-transglycosylases which catalyze
glycan chain elongation and peptidoglycan cross-links, while PBP 2 and
PBP 3 act only as transpeptidases. PBP 3 is essential for the formation
of the septum during cell division (8, 36, 37). PBP 2, encoded by the gene pbpA, is required for lateral cell wall
elongation and the maintenance of the rod shape (37). The
activity of PBP 2 accounts for about 70% of peptidoglycan synthesis
during elongation, indicating that PBP 2 is a major factor in net
synthesis (32). Inhibition of PBP 2 with mecillinam leads to
spherical cells and causes cell lysis after some generations (28). Mutations in the pbpA gene abolish
-lactamase induction (30).
TABLE 1.
Bacterial strains used in the study
Low-molecular-weight PBPs 4, 5, 6a, 6b, and 7 are dispensable, as their inactivation by mutation does not affect the vitality of the cells (1, 7). Most of the nonessential PBPs function as DD-carboxypeptidases. The DD-carboxypeptidases PBPs 4, 5, and 6 account for about 50% of the penicillin-binding capacity of bacterial cells (6). These enzymes are responsible for the degradation of the pentapeptide side chains to tetrapeptide in the peptidoglycan (1, 4, 36). Only newly inserted murein components carry pentapeptide side chains, which are rapidly degraded by transpeptidases and carboxypeptidases (4, 9). The inhibition of DD-carboxypeptidase leads to an increased level of pentapeptide side chains in the murein sacculus (1, 4, 7).
On the basis of our experiments we postulate that the
1,6-anhydromuramyl-pentapeptide is the main signal molecule for
-lactamase induction (5), for which it sends a signal by
converting AmpR from a repressor into an activator (16).
Strong inducers of -lactamase like imipenem and cefoxitin bind to
the DD-carboxypeptidases besides the essential PBPs and
lead to conservation of pentapeptide side chains in the murein
(5).
Here we describe induction studies performed with E. coli mutants lacking PBPs with carboxypeptidase activity (Table 1) which were transformed with the Enterobacter cloacae ampR-ampC operon.
Culture conditions. The E. coli strains were grown in M9 medium supplemented with glucose (0.2%), Casamino Acids (0.1%), thiamine (1 µg/ml), uracil (50 µg/ml), nicotinamide (5 µg/ml), and MgSO4 (1 mM) at 37°C. When required, sulfamethoxazole (1,000 µg/ml), neomycin (50 µg/ml), and tetracycline (50 µg/ml) were added.
The various antibiotics, which were tested for their capacity to induce the AmpC-lactamase, were kindly provided by the following
companies: cefotaxime by HMR Hoechst, Frankfurt, Germany; imipenem by
Merck Sharp & Dohme, West Point, Pa.; mecillinam by Leo Pharmaceutical
Products, Ballerup, Denmark; and aztreonam and cefsulodin by
Grünenthal, Aachen, Germany.
Antibiotic susceptibility testing.
Antibiotic susceptibility
was tested by a microdilution procedure in Iso-Sensitest broth
(Oxoid). MICs were determined with a photometer for
microtiter plates (Labsystems Multiscan Multisoft) after inoculation of
antibiotic-containing microtiter plates (Merlin-Diagnostika, Bornheim,
Germany) with 100 µl of an appropriate bacterial suspension (
105 CFU/ml) and incubation for 24 h at 36 ± 1°C.
Determination of -lactamase activity.
We performed
induction studies with E. coli PBP deletion mutants
transformed with plasmid pBP131 containing the E. cloacae genes (ampC and ampR) required for the expression
of E. cloacae -lactamase (19). The cells were
grown to an optical density at 546 nm (OD546) of 0.5, and
various antibiotics were added at concentrations that were half the MIC
for 40 min. As a positive control imipenem was added at 1 µg/ml.
Then, the cells (10 ml) were harvested by centrifugation at 4°C. The
cells were resuspended in 1 ml of 0.05 M potassium phosphate buffer (pH
7.0) and were frozen overnight. Sonication on ice with a Branson
sonifier yielded the cell extract for -lactamase determination. The
-lactamase activity was quantified as described by Peter et al.
(33), with nitrocefin (50 µM) used as the substrate
(29). The protein content of each sample was determined by
the method of Lowry et al. (26), with bovine serum albumin
used as the standard.
Role of PBPs for initiation of -lactamase induction.
The
MICs of most of the -lactamase-sensitive antibiotics were increased
only for UGM602 (PBP 5, 6a, and 6b negative) and the quadruple PBP
deletion mutant UGM603 (PBP 4, 5, 6a, and 6b negative) (1)
(Table 2). These results were a hint that
the basal -lactamase activity had changed.
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-lactamase level. However, the basal
-lactamase level is increased in the triple mutant UGM602 and is
especially increased in the quadruple mutant UGM603. The basal
-lactamase activity is elevated 2- to 3-fold in the triple
mutant UGM602 compared to that in the wild type or the mutants with
only one or two deletions of DD-carboxypeptidases and
is elevated 10-fold in the quadruple mutant (Table
3).
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-lactamase induction only in UGM603. The use of higher
concentrations of mecillinam and cefsulodin results in the same effect
(data not shown). The inhibition of PBP 3 by aztreonam (24)
had no consequence for the -lactamase induction (Table 3). Also, we
have tested a mutant that lacks PBPs 4, 5, and 6a, the effect for that
mutant was the same as that for UGM603 (data not shown).
These results suggest that only the deletion of three or four
DD-carboxypeptidases and the concomitant inhibition of the
essential PBP 1a, 1b, and/or 2 results in an increased level of
-lactamase induction. Thus, a strong inducer must inhibit all
DD-carboxypeptidases as well as essential PBPs 1a, 1b,
and/or 2. In contrast, Sanders et al. (35) suggested a major
role for PBP 4 in the induction of AmpC, as in PBP 4-negative and in
PBP 4- and PBP 7-negative mutants the inducibility decreases.
On the basis of these results we favor a modified model of the
induction of -lactamase that emphasizes the involvement of PBPs in this process (5, 17). In the periplasmic space
the -lactam antibiotics bind to PBPs, causing an imbalance in
the equilibrium of peptidoglycan synthesis and hydrolysis reactions (12). Four different lytic transglycosylases in E. coli are known to be associated with PBPs that bind to multienzyme
complexes. These lytic transglycosylases hydrolyze glycosidic bonds to
allow murein expansion, releasing muropeptides containing
anhydromuramic acid. All four enzymes function as exomuraminidases
which cleave the glycan strands in a processive manner starting at the
nonreducing glucosamine end. Three enzymes (MltA, MltB, and MltC) are
lipoproteins bound to the outer membrane, while Slt70 is a soluble
protein (12, 13, 25, 34, 39). Slt70 interacts with the
high-molecular-weight PBPs 1a, 1b, and 2 (39). The
three-dimensional structure of Slt70 revealed by X-ray crystallography
is doughnutlike, with the active site facing the inside
(38). It is suggested that peptide cross-links prevent
access of Slt70 to the glycan chains and therefore slow down the
activity of this enzyme (2). Inhibition of Slt70 leads to a
decrease in the level of -lactamase induction (Pfeifle et al., 38th
ICAAC; D. Pfeifle, I. Wiegand, and B. Wiedemann, Program Abstr. 9th
Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. 01174, 1999).
Inactivation of DD-carboxypeptidases PBP 4, 5, 6a, and 6b
leads to an increase in the level of pentapeptide side chains in the
peptidoglycan. Inhibition of PBP 1a, 1b, and/or 2 leads to inactivation
of the transpeptidase function, causing a decrease in the level of
cross-links in the murein. The reduced amount of cross-links allows
further degradation of the murein by the lytic transglycosylases
especially by Slt70 (39, 40). Therefore, degradation of the
murein sacculus is followed by an accumulation of aM peptides in
the periplasm. The most important degradation product, aM-pentapeptide,
is transported into the cytoplasm (5), where it probably
converts AmpR from a repressor into an activator of
ampC expression by displacing the UDP-NAcMur-pentapeptide
(uridine diphosphate-N-acetylmuramyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid-D-alanyl-D-alanine) from AmpR
(16).
Although the process of -lactamase induction is much better
understood in the context of peptidoglycan degradation and
recycling, we still lack knowledge about some essential steps of
-lactamase initiation. Studies will be needed to assess the
links between inhibition of PBPs, lytic transglycosylases, and
-lactamase induction. Inhibition of the lytic transglycosylases,
especially Slt70, could be a possible means of disturbing -lactamase
induction (Pfeifle et al., 9th ECCMID).
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ACKNOWLEDGMENTS |
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We are grateful to M.-R. Baquero, M. Bouzon, J. C. Quintela, J. Ayala, J. A. Ayala, and J. Moreno, for bacterial strains. We thank J. V. Höltje, Helgard Dietz, Irith Wiegand, and Volker Hüllen for active support and discussion.
This work was supported by a grant (grant WI 361/15-2) from the Deutsche Forschungsgemeinschaft; by Pfizer AG, Karlsruhe, Germany; and by Pinguin Stiftung, Düsseldorf, Germany.
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FOOTNOTES |
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* Corresponding author. Mailing address: Pharmazeutische Mikrobiologie, University of Bonn, Meckenheimer Allee 168, 53115 Bonn, Germany. Phone: (0228) 735272. Fax: (0228) 735267. E-mail: b.wiedemann{at}uni-bonn.de.
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Antimicrobial Agents and Chemotherapy, January 2000, p. 169-172, Vol. 44, No. 1
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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