Inactivation of Bacterial <scp>dd</scp>-Peptidase by β-Sultams

Llinàs, Antonio; Ahmed, Naveed; Cordaro, Massimiliano; Laws, Andrew P.; Frère, Jean Marie; Delmarcelle, Michaël; Silvaggi, N.R.; Kelly, Judith A.; Page, Michael I.

doi:10.1021/bi050110o

Cited by 34 publications

(28 citation statements)

References 35 publications

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“…This type of reaction has precedent in the literature, having been observed for the functionally homologous tricorn proteases [22], and the structurally homologous carboxylesterases [23]. Indeed, sulphonyl analogues of β-lactams have been shown to react with the highly-homologous beta-lactamase family [24]. Such a reaction with a buffer molecule with a relatively poor leaving group (H 2 O) would indicate a high reactivity of S70.…”

Section: Resultsmentioning

confidence: 86%

Specialized Peptidoglycan Hydrolases Sculpt the Intra-bacterial Niche of Predatory Bdellovibrio and Increase Population Fitness

et al. 2012

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Bdellovibrio are predatory bacteria that have evolved to invade virtually all Gram-negative bacteria, including many prominent pathogens. Upon invasion, prey bacteria become rounded up into an osmotically stable niche for the Bdellovibrio, preventing further superinfection and allowing Bdellovibrio to replicate inside without competition, killing the prey bacterium and degrading its contents. Historically, prey rounding was hypothesized to be associated with peptidoglycan (PG) metabolism; we found two Bdellovibrio genes, bd0816 and bd3459, expressed at prey entry and encoding proteins with limited homologies to conventional dacB/PBP4 DD-endo/carboxypeptidases (responsible for peptidoglycan maintenance during growth and division). We tested possible links between Bd0816/3459 activity and predation. Bd3459, but not an active site serine mutant protein, bound β-lactam, exhibited DD-endo/carboxypeptidase activity against purified peptidoglycan and, importantly, rounded up E. coli cells upon periplasmic expression. A ΔBd0816 ΔBd3459 double mutant invaded prey more slowly than the wild type (with negligible prey cell rounding) and double invasions of single prey by more than one Bdellovibrio became more frequent. We solved the crystal structure of Bd3459 to 1.45 Å and this revealed predation-associated domain differences to conventional PBP4 housekeeping enzymes (loss of the regulatory domain III, alteration of domain II and a more exposed active site). The Bd3459 active site (and by similarity the Bd0816 active site) can thus accommodate and remodel the various bacterial PGs that Bdellovibrio may encounter across its diverse prey range, compared to the more closed active site that “regular” PBP4s have for self cell wall maintenance. Therefore, during evolution, Bdellovibrio peptidoglycan endopeptidases have adapted into secreted predation-specific proteins, preventing wasteful double invasion, and allowing activity upon the diverse prey peptidoglycan structures to sculpt the prey cell into a stable intracellular niche for replication.

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Section: Resultsmentioning

confidence: 86%

Specialized Peptidoglycan Hydrolases Sculpt the Intra-bacterial Niche of Predatory Bdellovibrio and Increase Population Fitness

et al. 2012

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“…[13] To our delight, when we carried out the reaction with Et 3 N in CH 2 Cl 2 , we achieved high yield, regioselectivity and diastereoselectivity (entry 1, Table 1). The only isolated Table 1.…”

Section: Introductionmentioning

confidence: 97%

Highly Regio‐ and Diastereoselective Oxazol‐5‐one Addition to Nitrostyrenes

et al. 2009

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“…The field is dominated by the β-lactams (1) [ Figure 1] due to the importance that they have acquired as anti-infective agents. [1][2][3] The corresponding β-sultams (2) are also known and have attracted attention as taurine precursors, 4,5 β-lactamase inhibitors, 6 D,D-peptidase inhibitors, 7 human neutrophil elastase inhibitors, [8][9][10] azoreductase inhibitors, 11 anti-inflammatory agents, 12 potential treatments for alcohol dependency, 13 SPase I inhibitors 14 and ClpP protease inhibitors, 15 and have attracted other mechanistic 16,17 and synthetic efforts. [18][19][20] β-Sultam chemistry been a focus of our research for some time.…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20] β-Sultam chemistry been a focus of our research for some time. [6][7][8][9][10]12,13,17 …”

Section: Introductionmentioning

confidence: 99%

Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides

et al. 2016

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Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low μM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

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Inactivation of Bacterial dd-Peptidase by β-Sultams

Cited by 34 publications

References 35 publications

Specialized Peptidoglycan Hydrolases Sculpt the Intra-bacterial Niche of Predatory Bdellovibrio and Increase Population Fitness

Specialized Peptidoglycan Hydrolases Sculpt the Intra-bacterial Niche of Predatory Bdellovibrio and Increase Population Fitness

Highly Regio‐ and Diastereoselective Oxazol‐5‐one Addition to Nitrostyrenes

Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides

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