Chapter 23 Mechanisms of chromosomal β-lactamase induction in Gram-negative bacteria

Normark, Staffan; Bartowsky, Eveline; Erickson, Jay; Jacobs, Christine; Lindberg, Frederik P.; Lindquist, Susanne; Weston-Hafer, Kathleen; Wikström, Mikael

doi:10.1016/s0167-7306(08)60426-3

Cited by 27 publications

(32 citation statements)

References 71 publications

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“…Recycling is a major metabolic pathway of the cell, which utilizes over 1,000,000 molecules of murein tripeptide per generation. The fact that AmpG and AmpD, essential components of the inducible ␤-lactamase system of many bacteria (23), are present in E. coli, a bacterium which lacks an inducible ␤-lactamase, has led to speculation that recycling may be a way in which the cell monitors the condition of its cell wall (i.e., fluctuations in the concentration of recycling intermediates may signal, for example, whether the cell should continue growth or commit to stationary phase) (26). Mpl would also be part of this hypothetical regulatory circuit.…”

Section: Discussionmentioning

confidence: 99%

Identification of the mpl gene encoding UDP-N-acetylmuramate: L-alanyl-gamma-D-glutamyl-meso-diaminopimelate ligase in Escherichia coli and its role in recycling of cell wall peptidoglycan

1996

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A gene, mpl, encoding UDP-N-acetylmuramate:L-alanyl-␥-D-glutamyl-meso-diaminopimelate ligase was recognized by its amino acid sequence homology with murC as the open reading frame yjfG present at 96 min on the Escherichia coli map. The existence of such an enzymatic activity was predicted from studies indicating that reutilization of the intact tripeptide L-alanyl-␥-D-glutamyl-meso-diaminopimelate occurred and accounted for well over 30% of new cell wall synthesis. Murein tripeptide ligase activity could be demonstrated in crude extracts, and greatly increased activity was produced when the gene was cloned and expressed under control of the trc promoter. A null mutant totally lacked activity but was viable, showing that the enzyme is not essential for growth.The biosynthesis of bacterial cell wall peptidoglycan (murein) is a complex process involving many different cytoplasmic and membrane steps (for review, see references 11, 24, and 30). The main cytoplasmic precursors of Escherichia coli are a series of seven uridine nucleotides, from UDP-N-acetylglucosamine to UDP-N-acetylmuramyl-L-Ala-␥-D-Glu-meso-A 2 pm-D-Ala-D-Ala (where A 2 pm represents diaminopimelic acid). Their sequential formation is catalyzed by a set of highly specific enzymes, designated as Mur activities (MurA to MurF [ Fig. 1]). Subsequent steps located in the membrane result in the synthesis of the disaccharide pentapeptide MurNAc(-pentapeptide)-GlcNAc, which is anchored in the membrane via the lipid carrier undecaprenyl-phosphate. The disaccharide pentapeptide units are then used in polymerization reactions (transglycosylation and transpeptidation) catalyzed by the wellknown bifunctional penicillin-binding proteins. In order to enlarge the murein sacculus during normal cell growth and division, new peptidoglycan subunits have to be inserted into the preexisting network, a process which probably begins with a specific cleavage of some covalent bonds by peptidoglycan hydrolases (9,29).A large portion of the murein sacculus of E. coli is degraded each generation, resulting in the formation of various degradation products which can be detected in the culture medium (8). One of them, the tripeptide L-alanyl-␥-D-glutamyl-meso-A 2 pm, is of particular interest, since it was shown to be efficiently reutilized by the cell to form new cell wall murein via a reaction sequence termed "the recycling pathway" (6-8, 25, 26). This pathway involves five different known hydrolases and a permease. However, reutilization of the tripeptide was ultimately dependent on a hypothetical ligase which could link tripeptide to UDP-N-acetylmuramic acid (Fig. 1). This paper demonstrates the existence of such an enzyme and presents the initial characterization of its properties as well as identification and mapping of its gene, mpl (which codes for murein peptide ligase). MATERIALS AND METHODSBacterial strains, plasmids, and growth conditions. The E. coli strains used in this study are listed in Table 1. Plasmid pFD12, a pBR322 derivative carrying an 18.5-kb chromosomal fr...

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Section: Discussionmentioning

confidence: 99%

Identification of the mpl gene encoding UDP-N-acetylmuramate: L-alanyl-gamma-D-glutamyl-meso-diaminopimelate ligase in Escherichia coli and its role in recycling of cell wall peptidoglycan

1996

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“…In many gram-negative organisms, class I ␤-lactamase is induced by certain ␤-lactam antibiotics, such as cefoxitin and imipenem, as well as some nonspecific inducers (9,26,30). Citrobacter freundii and Enterobacter cloacae have been the principal bacteria studied.…”

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confidence: 99%

“…AmpR belongs to the LysR family of bacterial regulators. The proteins of this family have a helix-turn-helix DNA-binding motif at the N-terminal region and a cofactor-binding domain (26). Jacobs et al (13), employing an in vitro transcription assay, showed that AmpR is an activator for ampC expression.…”

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Role of the Murein Precursor UDP- N -Acetylmuramyl- l -Ala-γ- d -Glu- meso -Diaminopimelic Acid- d -Ala- d -Ala in Repression of β-Lactamase Induction in Cell Division Mutants

Uehara

Park

2002

J Bacteriol

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Certain ␤-lactam antibiotics induce the chromosomal ampC ␤-lactamase of many gram-negative bacteria. The natural inducer, though not yet unequivocally identified, is a cell wall breakdown product which enters the cell via the AmpG permease component of the murein recycling pathway. Surprisingly, it has been reported that ␤-lactamase is not induced by cefoxitin in the absence of FtsZ, which is required for cell division, or in the absence of penicillin-binding protein 2 (PBP2), which is required for cell elongation. Since these results remain unexplained, we examined an ftsZ mutant and other cell division mutants (ftsA, ftsQ, and ftsI) and a PBP2 mutant for induction of ␤-lactamase. In all mutants, ␤-lactamase was not induced by cefoxitin, which confirms the initial reports. The murein precursor, UDP-N-acetylmuramyl-L-Ala-␥-D-Glu-meso-diaminopimelic acid-D-Ala-D-Ala (UDP-MurNAc-pentapeptide), has been shown to serve as a corepressor with AmpR to repress ␤-lactamase expression in vitro. Our results suggest that ␤-lactamase is not induced because the fts mutants contain a greatly increased amount of corepressor which the inducer cannot displace. In the PBP2(Ts) mutant, in addition to accumulation of corepressor, cell wall turnover and recycling were greatly reduced so that little or no inducer was available. Hence, in both cases, a high ratio of repressor to inducer presumably prevents induction.

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“…This is recognized as a major factor of p-lactam resistance in these organisms. Molecular studies of the induction process have revealed many properties and functions of the structural and regulatory genes involved (Normark et al, 1990(Normark et al, , 1994. The more recently discovered gene ampG (Korfmann & Sanders, 1989 ; Lindquist e t al.…”

Section: Introductionmentioning

confidence: 99%

The signal transducer encoded by ampG is essential for induction of chromosomal AmpC -lactamase in Escherichia coli by -lactam antibiotics and unspecific inducers

et al. 1995

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Chapter 23 Mechanisms of chromosomal β-lactamase induction in Gram-negative bacteria

Cited by 27 publications

References 71 publications

Identification of the mpl gene encoding UDP-N-acetylmuramate: L-alanyl-gamma-D-glutamyl-meso-diaminopimelate ligase in Escherichia coli and its role in recycling of cell wall peptidoglycan

Identification of the mpl gene encoding UDP-N-acetylmuramate: L-alanyl-gamma-D-glutamyl-meso-diaminopimelate ligase in Escherichia coli and its role in recycling of cell wall peptidoglycan

Role of the Murein Precursor UDP- N -Acetylmuramyl- l -Ala-γ- d -Glu- meso -Diaminopimelic Acid- d -Ala- d -Ala in Repression of β-Lactamase Induction in Cell Division Mutants

The signal transducer encoded by ampG is essential for induction of chromosomal AmpC -lactamase in Escherichia coli by -lactam antibiotics and unspecific inducers

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