Distribution of the Mosaic Structured
            <i>murM</i>
            Genes among Natural Populations of
            <i>Streptococcus pneumoniae</i>

Filipe, Sérgio R.; Severina, Elena; Tomasz, Alexander

doi:10.1128/jb.182.23.6798-6805.2000

Cited by 44 publications

(55 citation statements)

References 18 publications

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“…s and ᮀ, Pen6 and Pen6murMN without antibiotics, respectively; ࡗ and छ, Pen6 and Pen6murMN with 50 g͞ml DOC, respectively; OE and ‚, Pen6 and Pen6murMN with 100 g͞ml DOC, respectively. the chemical composition of the branched peptides in various transformants differed depending on the source of the particular murM allele (3,5). Serine-rich branched peptides were produced in transformants that received murM from strain KY17, whereas transformants with the murM strain from DE1 produced alanine-rich branches.…”

Section: Discussionmentioning

confidence: 99%

“…The genetic determinants involved with the branching process, the murMN operon, were identified recently (2). Penicillin-resistant isolates with highly branched cell walls were shown to carry murM alleles that contained divergent sequences as compared with the murM genes of penicillin-susceptible pneumococci (3). The two proteins, MurM (407 amino acids) and MurN (411 amino acids), are involved with the addition of the first and second amino acid residues, respectively, to the cell wall precursor stem peptide at the lipid II stage of biosynthesis (4,5).…”

Section: S Everal Penicillin-resistant Clones Of Streptococcus Pneumomentioning

confidence: 99%

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The murMN operon: A functional link between antibiotic resistance and antibiotic tolerance in Streptococcus pneumoniae

Filipe

Severina²,

Tomasz³

2002

Proc. Natl. Acad. Sci. U.S.A.

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Inactivation of the recently identified murMN operon in penicillinresistant strains of Streptococcus pneumoniae was shown already to cause two major effects: elimination of branched-structured muropeptides from the cell wall and complete loss of penicillin resistance. We now show that cells with inactivated murMN also have a third phenotype: an increased susceptibility to lysis when exposed to low concentrations of fosfomycin, D-cycloserine, vancomycin, and nisin, indicating a wide-spectrum hypersensitivity to inhibitors of both early and late stages of cell wall biosynthesis. Mutants of murMN also lysed faster than the parental strain when treated with the detergent deoxycholate. Several different alleles of murM cloned in plasmid pLS578 and introduced into a murM deletion mutant of the penicillin-resistant strain Pen6 were able to reconstitute each one of the three mutant phenotypes: the highly branched cell wall structure, original high level of penicillin resistance, and normal sensitivity to lysis. In a penicillin-susceptible strain the same experiments caused increased concentration of cell wall branched peptides and suppression of sensitivity to antibiotic induced lysis. The observations suggest that the murMN operon plays a key role in the regulation of a stress-response pathway that can be triggered by perturbation of cell wall biosynthesis in S. pneumoniae. S everal penicillin-resistant clones of Streptococcus pneumoniaeproduce abnormal cell walls in which a high proportion of the stem peptide lysine residues carry short (seryl alanine or alanyl alanine) branches (1). The genetic determinants involved with the branching process, the murMN operon, were identified recently (2). Penicillin-resistant isolates with highly branched cell walls were shown to carry murM alleles that contained divergent sequences as compared with the murM genes of penicillin-susceptible pneumococci (3). The two proteins, MurM (407 amino acids) and MurN (411 amino acids), are involved with the addition of the first and second amino acid residues, respectively, to the cell wall precursor stem peptide at the lipid II stage of biosynthesis (4, 5). Inactivation of murMN by insertion-duplication mutagenesis did not interfere with growth of the bacteria but caused two phenotypes: elimination of branched peptides from the cell wall and complete loss of penicillin resistance (2). The purpose of the studies described in this communication was to follow up these earlier findings by the use of a deletion mutant of murM and complementation experiments. The surprising observation made was that inactivation of murM also caused a third phenotype: increased sensitivity of the bacteria to lysis by cell wall inhibitors. Experimental ProceduresStrains and Growth Conditions. All strains and plasmids used in this study are listed in Table 1. S. pneumoniae strains were grown in a casein-based semisynthetic medium (C ϩ Y) at 37°C without aeration as described (11). S. pneumoniae strains containing pLS578 (10) or its derivatives were grown in the presen...

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Section: Discussionmentioning

confidence: 99%

Section: S Everal Penicillin-resistant Clones Of Streptococcus Pneumomentioning

confidence: 99%

The murMN operon: A functional link between antibiotic resistance and antibiotic tolerance in Streptococcus pneumoniae

Filipe

Severina²,

Tomasz³

2002

Proc. Natl. Acad. Sci. U.S.A.

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“…pneumoniae strains producing mosaic PBP fusions often manufacture a peptidoglycan which is enriched in interpeptide cross-bridges (64,65). The inactivation of murMN in S. pneumoniae Pen6 (MIC, 6 g of benzylpenicillin ml Ϫ1 ), with loss of the enzymes of the pathway to branched peptidoglycan precursors (see the section on lipid II precursors), restores susceptibility to the drug (MIC, 0.03 g of benzylpenicillin ml Ϫ1 ).…”

Section: Mosaic Pbp Fusionsmentioning

confidence: 99%

Biochemistry and Comparative Genomics of SxxK Superfamily Acyltransferases Offer a Clue to the Mycobacterial Paradox: Presence of Penicillin-Susceptible Target Proteins versus Lack of Efficiency of Penicillin as Therapeutic Agent

Goffin

Ghuysen

2002

Microbiol Mol Biol Rev

179

213

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The bacterial acyltransferases of the SxxK superfamily vary enormously in sequence and function, with conservation of particular amino acid groups and all-α and α/β folds. They occur as independent entities (free-standing polypeptides) and as modules linked to other polypeptides (protein fusions). They can be classified into three groups. The group I SxxK d,d-acyltransferases are ubiquitous in the bacterial world. They invariably bear the motifs SxxK, SxN(D), and KT(S)G. Anchored in the plasma membrane with the bulk of the polypeptide chain exposed on the outer face of it, they are implicated in the synthesis of wall peptidoglycans of the most frequently encountered (4→3) type. They are inactivated by penicillin and other β-lactam antibiotics acting as suicide carbonyl donors in the form of penicillin-binding proteins (PBPs). They are components of a morphogenetic apparatus which, as a whole, controls multiple parameters such as shape and size and allows the bacterial cells to enlarge and duplicate their particular pattern. Class A PBP fusions comprise a glycosyltransferase module fused to an SxxK acyltransferase of class A. Class B PBP fusions comprise a linker, i.e., protein recognition, module fused to an SxxK acyltransferase of class B. They ensure the remodeling of the (4→3) peptidoglycans in a cell cycle-dependent manner. The free-standing PBPs hydrolyze d,d peptide bonds. The group II SxxK acyltransferases frequently have a partially modified bar code, but the SxxK motif is invariant. They react with penicillin in various ways and illustrate the great plasticity of the catalytic centers. The secreted free-standing PBPs, the serine β-lactamases, and the penicillin sensors of several penicillin sensory transducers help the d,d-acyltransferases of group I escape penicillin action. The group III SxxK acyltransferases are indistinguishable from the PBP fusion proteins of group I in motifs and membrane topology, but they resist penicillin. They are referred to as Penr protein fusions. Plausible hypotheses are put forward on the roles that the Penr protein fusions, acting as l,d-acyltransferases, may play in the (3→3) peptidoglycan-synthesizing molecular machines. Shifting the wall peptidoglycan from the (4→3) type to the (3→3) type could help Mycobacterium tuberculosis and Mycobacterium leprae survive by making them penicillin resistant

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“…The variability of the murMN genes appears to be responsible for variations in the catalytic efficiencies of their products (30,95). Again, in resistant strains, a larger amount of branched muropeptides indicates that these strains contain murM alleles that encode a highly efficient enzyme.…”

Section: Biosynthesis Of Branched Cell Wall Peptides and Impact On ␤-mentioning

confidence: 99%

FemABX Peptidyl Transferases: a Link between Branched-Chain Cell Wall Peptide Formation and β-Lactam Resistance in Gram-Positive Cocci

Rohrer

Berger‐Bächi

2003

Antimicrob Agents Chemother

106

102

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Distribution of the Mosaic Structured murM Genes among Natural Populations of Streptococcus pneumoniae

Cited by 44 publications

References 18 publications

The murMN operon: A functional link between antibiotic resistance and antibiotic tolerance in Streptococcus pneumoniae

The murMN operon: A functional link between antibiotic resistance and antibiotic tolerance in Streptococcus pneumoniae

Biochemistry and Comparative Genomics of SxxK Superfamily Acyltransferases Offer a Clue to the Mycobacterial Paradox: Presence of Penicillin-Susceptible Target Proteins versus Lack of Efficiency of Penicillin as Therapeutic Agent

FemABX Peptidyl Transferases: a Link between Branched-Chain Cell Wall Peptide Formation and β-Lactam Resistance in Gram-Positive Cocci

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