- Tabtoxinine-β-lactam is a "stealth" β-lactam antibiotic that evades β-lactamase-mediated antibiotic resistance
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Tabtoxinine-β-lactam (TβL) is a phytotoxin produced by plant pathogenic strains of Pseudomonas syringae. Unlike the majority of β-lactam antibiotics, TβL does not inhibit transpeptidase enzymes but instead is a potent, time-dependent inactivator of glutamine synthetase, an attractive and underexploited antibiotic target. TβL is produced by P. syringae in the form of a threonine dipeptide prodrug, tabtoxin (TβL-Thr), which enters plant and bacterial cells through dipeptide permeases. The role of β-lactamases in the self-protection of P. syringae from tabtoxin has been proposed, since this organism produces at least three β-lactamases. However, using in vitro and cellular assays and computational docking we have shown that TβL and TβL-Thr evade the action of all major classes of β-lactamase enzymes, thus overcoming the primary mechanism of resistance observed for traditional β-lactam antibiotics. TβL is a "stealth" β-lactam antibiotic and dipeptide prodrugs such as tabtoxin from P. syringae represent a novel antibiotic therapeutic strategy for treating multi-drug resistant Gram-negative pathogens expressing high levels of β-lactamase enzymes.
- Hart, Kathryn M.,Reck, Margaret,Bowman, Gregory R.,Wencewicz, Timothy A.
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p. 118 - 127
(2016/01/30)
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- Investigation of a Proposed Penicillin G Acidic Degradation Scheme using High-pressure Liquid Chromatography and Optimization Techniques and Mechanistic Considerations
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Optimization techniques were used to fit a recently proposed degradation scheme to recently published n.m.r. data for the time course of penicillin G and four degradation products at pH 2.5 and 37 deg C.Several conclusions arising from the n.m.r. analysis which were originally associated with the degradation scheme were not compatible with the optimized rate constants.It was necessary to change substantially the proportion of penicillin G degrading through benzylpenicillenic acid, benzylpenillic acid, and benzylpenicilloic acid in order for the degradation scheme to fit the n.m.r. data.Benzylpenillic acid replaced benzylpenicillenic acid as the major product.The rate constants best describing the n.m.r. data showed benzylpenicillenic acid proceeding almost exclusively through benzylpenamaldic acid.Such optimization implied that the scheme could be simplified to three parallel reaction pathways, the dominant reaction occurring through benzylpenillic acid.However, mechanistic considerations indicate that the direct conversion of penicillin G into benzylpenillic acid is not possible and that a likely intermediate is benzylpenicilloic acid.The degradation of benzylpenicilloic acid at pH 2.5 was consequently monitored by ionpair reversed-phase high-pressure liquid chromatography and rapid formation of benzylpenillic acid was detected.This observation is inconsistent with the recently proposed degradation scheme, even though the scheme can be made to fit the n.m.r. kinetic data.
- Kessler, David P.,Cushman, Mark,Ghebre-Sellassie, Isaac,Knevel, Adelbert M.,Hem, Stanley L.
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p. 1699 - 1704
(2007/10/02)
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- The Micelle-catalysed Hydrolysis of Benzylpenicillin
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Micelles of cetyltrimethylammonium bromide catalyse the alkaline hydrolysis of benzylpenicillin with a rate enhancement of ca. 50-fold.Howewer, the rate of reaction is inhibited by increasing concentrations of hydroxide ion and penicillin anion.A saturation phenomenon is observed with increased concentration of surfactant.Attempts are made to determine the binding- and rate-constants using existing kinetic models.These are not completely satisfactory and a model is proposed which assumes that both hydroxide ion and penicillin have to be bound to the micelle for reaction to occur.Bromide, chloride, acetate, fluoride, and benzylpenicilloate ions all inhibit the micellar catalysis.
- Gensmantel, Nigel P,Page, Michael I.
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p. 147 - 154
(2007/10/02)
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- The Chemical Reactivity of Penicillins and Other β-Lactam Antibiotics
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The rates of the acid catalysed hydrolysis of penicillins and cephalosporins are linear in Ho and, unlike other amides, show no rate maximum with increasing acidity.Electron-withdrawing substituents at C-6 in penicillins decrease the rate of hydrolysis with a ρI of ca. 4 and they decrease the rate when attached to the amine leaving group.The acylamido-group at C-6 in penicillins, but not at C-7 in cephalosporins, exhibits neighbouring group participation with a rate enhancement of ca. 103.The absence of penicillenic acid formation from benzylpenicillin in acidic solution is not due to the ionisation of the carboxy-group.These observations are rationalised by a scheme involving N-protonation and formation of an acylium ion intermediate.The alkaline hydrolysis of penicillins proceeds 102 faster than a β-lactam after correction for substituent effects.There is no evidence for substantial inhibition of amide resonance in the bicyclic β-lactam antibiotics, little evidence to indicate extra strain in these systems and no evidence that expulsion of the leaving group at C-3 in cephalosporins occurs in the transition state.
- Proctor, Philip,Gensmantel, Nigel P.,Page, Michael I.
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p. 1185 - 1192
(2007/10/02)
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- Intra- and Inter-molecular Catalysis in the Aminolysis of Benzylpenicillin
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The rate law for the aminolysis of benzylpenicillin in water is reported.The Bronsted β-values for the uncatalysed, the amine-catalysed, and hydroxide-ion catalysed reactions are 1.0, 1.09, and 0.96 respectively.This indicates that in the transition states for all three pathways the amine nucleophile contains a unit positive charge which is consistent with the formation of a tetrahedral intermediate.Intramolecular general base catalysis occurs with the reaction of ethylenediamine and, despite the importance of general base catalysis in the aminolysis reaction, the effective concentration of the catalysing base is only ca. 1M, which is attributed to the 'loose' transition state involved in intermolecular catalysis.Intramolecular general acid catalysis occurs with the reaction of ethylenediamine monocation.This suggests that nucleophilic attack takes place from the least hindered α-side.
- Morris, Jeffrey J.,Page, Michael I.
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p. 212 - 219
(2007/10/02)
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