Discrete and overlapping functions of peptidoglycan synthases in growth, cell division and virulence of <scp><i>L</i></scp><i>isteria monocytogenes</i>

Rismondo, Jeanine; Møller, Lars; Aldridge, Christine; Gray, Joe; Vollmer, Waldemar; Halbedel, Sven

doi:10.1111/mmi.12873

Cited by 36 publications

(64 citation statements)

References 53 publications

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“…Simultaneous inactivation of the two bi‐functional PBPs, Lm PBP A1 and Lm PBP A2, is not tolerated by L. monocytogenes (Rismondo et al ., ), providing a means to determine if Lm GpsB is required for Lm PBP A1 activity. Despite repeated attempts, we were unable to generate a Δ gpsB mutant that also lacked pbpA2 , indicating synthetic lethality of both genes.…”

Section: Resultsmentioning

confidence: 99%

Structure of the bacterial cell division determinant GpsB and its interaction with penicillin‐binding proteins

Rismondo

Cleverley

Lane

et al. 2015

Molecular Microbiology

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203

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SummaryEach bacterium has to co-ordinate its growth with division to ensure genetic stability of the population. Consequently, cell division and growth are tightly regulated phenomena, albeit different bacteria utilise one of several alternative regulatory mechanisms to maintain control. Here we consider GpsB, which is linked to cell growth and division in Gram-positive bacteria. ΔgpsB mutants of the human pathogen Listeria monocytogenes show severe lysis, division and growth defects due to distortions of cell wall biosynthesis. Consistent with this premise, GpsB interacts both in vitro and in vivo with the major bi-functional penicillin-binding protein. We solved the crystal structure of GpsB and the interaction interfaces in both proteins are identified and validated. The inactivation of gpsB results in strongly attenuated virulence in animal experiments, comparable in degree to classical listerial virulence factor mutants. Therefore, GpsB is essential for in vitro and in vivo growth of a highly virulent food-borne pathogen, suggesting that GpsB could be a target for the future design of novel antibacterials.

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Section: Resultsmentioning

confidence: 99%

Structure of the bacterial cell division determinant GpsB and its interaction with penicillin‐binding proteins

Rismondo

Cleverley

Lane

et al. 2015

Molecular Microbiology

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203

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“…On the other hand, some of the high molecular weight PBPs have transglycosylase activity and, again, they can substitute for each other (Rismondo et al . ). Consequently, the integrity of the cell wall murein is retained, sometimes at the cost of certain structural modifications.…”

Section: The General Characteristics Of the Penicillin‐binding Proteimentioning

confidence: 97%

“…; Rismondo et al . ). Unfortunately, the susceptibility to cephalosporins of conditional and deletion mutants in genes encoding HMM PBP was not examined.…”

Section: The Role Of Pbps In the Intrinsic Resistance Of Listeria Monmentioning

confidence: 97%

The intrinsic cephalosporin resistome of Listeria monocytogenes in the context of stress response, gene regulation, pathogenesis and therapeutics

Krawczyk‐Balska

Markiewicz

2015

J Appl Microbiol

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Summary Intrinsic resistance to antibiotics is a serious therapeutic problem in the case of many bacterial species. The Gram‐positive human pathogen Listeria monocytogenes is intrinsically resistant to broad spectrum cephalosporin antibiotics, which are commonly used in therapy of bacterial infections. Besides three penicillin‐binding proteins the intrinsic cephalosporin resistome of L. monocytogenes includes multidrug resistance transporter transporters, proteins involved in peptidoglycan biosynthesis and modification, cell envelope proteins with structural or general detoxification function, cytoplasmic proteins with unknown function and regulatory proteins. Analysis of the regulation of the expression of genes involved in the intrinsic resistance of L. monocytogenes to cephalosporins highlights the high complexity of control of the intrinsic resistance phenotype. The regulation of the transcription of the intrinsic resistome determinants involves the activity of eight regulators, namely LisR, CesR, LiaR, VirR, σB, σH, σL and PrfA, of which the most prominent role play LisR, CesR and σB. Furthermore, the vast majority of the intrinsic resistome determinants contribute to the tolerance of different stress conditions and virulence. A study indicates that O‐acetyltransferase OatA is the most promising candidate for co‐drug development since an agent targeting OatA should sensitize L. monocytogenes to certain antibiotics, therefore improving the efficacy of listeriosis treatment as well as food preservation measures.

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“…GpsB interacts with PBP A1, and this interaction is required for PBP A1 function (10). PBP A1 is one of two bifunctional penicillin binding proteins in L. monocytogenes (8,32), and at least one of them, either PBP A1 or PBP A2, must be present for viability (9). PBP A1 seems to be important for cell wall biosynthesis during cell division, since deletion of the pbpA1 gene clearly caused cell elongation, whereas deletion of pbpA2 did not cause such an effect (9).…”

Section: Discussionmentioning

confidence: 99%

Suppressor Mutations LinkinggpsBwith the First Committed Step of Peptidoglycan Biosynthesis in Listeria monocytogenes

2017

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The cell division protein GpsB is a regulator of the penicillin binding protein A1 (PBP A1) in the Gram-positive human pathogen Listeria monocytogenes. Penicillin binding proteins mediate the last two steps of peptidoglycan biosynthesis as they polymerize and cross-link peptidoglycan strands, the main components of the bacterial cell wall. It is not known what other processes are controlled by GpsB. L. monocytogenes gpsB mutants are unable to grow at 42°C, but we observed that spontaneous suppressors correcting this defect arise on agar plates with high frequency. We here describe a first set of gpsB suppressors that mapped to the clpC and murZ genes. While ClpC is the ATPase component of the Clp protease, MurZ is a paralogue of the listerial UDP-N-acetylglucosamine (UDPGlcNAc) 1-carboxyvinyltransferase MurA. Both enzymes catalyze the enolpyruvyl transfer from phosphoenolpyruvate to UDP-GlcNAc, representing the first committed step of peptidoglycan biosynthesis. We confirmed that clean deletion of the clpC or murZ gene suppressed the ΔgpsB phenotype. It turned out that the absence of either gene leads to accumulation of MurA, and we show that artificial overexpression of MurA alone was sufficient for suppression. Inactivation of other UDP-GlcNAcconsuming pathways also suppressed the heat-sensitive growth of the ΔgpsB mutant, suggesting that an increased influx of precursor molecules into peptidoglycan biosynthesis can compensate for the lack of GpsB. Our results support a model according to which PBP A1 becomes misregulated and thus toxic in the absence of GpsB due to unproductive consumption of cell wall precursor molecules. IMPORTANCEThe late cell division protein GpsB is important for cell wall biosynthesis in Gram-positive bacteria. GpsB of the human pathogen L. monocytogenes interacts with one of the key enzymes of this pathway, penicillin binding protein A1 (PBP A1), and influences its activity. PBP A1 catalyzes the last two steps of cell wall biosynthesis, but it is unknown how GpsB controls PBP A1. We observed that a L. monocytogenes gpsB mutant forms spontaneous suppressors and have mapped their mutations to genes mediating and influencing the first step of cell wall biosynthesis, likely stimulating the influx of metabolites into this pathway. We assume that GpsB is important to ensure productive incorporation of cell wall precursors into the peptidoglycan sacculus by PBP A1.KEYWORDS GpsB, MurA, UDP-N-acetylglucosamine, PBP A1, peptidoglycan, UDP-N-acetylglucosamine T he cell wall represents the outmost layer of the bacterial envelope in Gram-positive bacteria. It confers rigidity and shape to their cells and provides a platform for incorporation of many molecules, e.g., proteins and wall teichoic acids, which need to be presented on the bacterial surface (1-3). The Gram-positive cell wall consists of a

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Discrete and overlapping functions of peptidoglycan synthases in growth, cell division and virulence of Listeria monocytogenes

Cited by 36 publications

References 53 publications

Structure of the bacterial cell division determinant GpsB and its interaction with penicillin‐binding proteins

Structure of the bacterial cell division determinant GpsB and its interaction with penicillin‐binding proteins

The intrinsic cephalosporin resistome of Listeria monocytogenes in the context of stress response, gene regulation, pathogenesis and therapeutics

Suppressor Mutations LinkinggpsBwith the First Committed Step of Peptidoglycan Biosynthesis in Listeria monocytogenes

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