Synthesis, Hydrolysis, and Evaluation of 3-Acylamino-3,4-dihydro-2-oxo-2H-1,3-benzoxazinecarboxylic Acids and Linear Azadepsipeptides as Potential Substrates/Inhibitors of β-Lactam-Recognizing Enzymes

Cabaret, D.; González, Miguel; Wakselman, Michel; Adediran, S. A.; Pratt, Robertson

doi:10.1002/1099-0690(200101)2001:1<141::aid-ejoc141>3.0.co;2-j

Cited by 14 publications

(2 citation statements)

References 47 publications

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“…Similar pKa values have been reported for reactions of the P99 β-lactamase (kcat/Km) with substrates, e.g. 5.85 ± 0.09, 5.92 ± 0.16, 6.21 ± 0.11, 5.89 ± 0.07 and 6.29 ± 0.04 (24,25). The important consequence of the pH profile of Figure 3, which is presumably very similar to those for 3 – 8 because of their similar pK a2 values (see above), is that the maximal activity of these inhibitors is expressed at around pH 6.2 and thus the data of Table1, taken at pH 7.5, does not reflect their absolute potency [e.g.…”

Section: Resultssupporting

confidence: 83%

“…120° found in penicillins (38), for example, would therefore be only accessible to 1 after surmounting an energy barrier of several kilocalories (39). We have previously reported that the X = NH analogues of 1 , where the barrier would be even higher, are not substrates or inhibitors of the P99 β-lactamase or of the structurally similar Streptomyces R61 DD-peptidase (24). The limited conformational accessibility of the β-lactamase active site has been previously discussed (40).…”

Section: Resultsmentioning

confidence: 99%

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Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Pelto

Pratt

2008

Biochemistry

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The class C serine β-lactamase of Enterobacter cloacae P99 is irreversibly inhibited by Oaryloxycarbonyl hydroxamates. A series of these new inhibitors has been prepared to investigate the kinetics and mechanism of the inactivation reaction. A pH-rate profile for the reaction indicated that the reactive form of the inhibitor is neutral rather than anionic. The reaction rate is enhanced by electron-withdrawing aryloxy substituents and by hydrophobic substitution on both aryloxy and hydroxamate groups. Kinetics studies show that the rates of loss of the two possible leaving groups, aryloxide and hydroxamate are essentially the same as the rate of enzyme inactivation. Nucleophilic trapping experiments prove, however, that the aryloxide is the first to leave. It is likely, therefore, that the rate-determining step of inactivation is the initial acylation reaction, most likely of the active site serine, yielding a hydroxamoyl-enzyme intermediate. This then partitions between hydrolysis and aminolysis by Lys 315, the latter to form an inactive, cross-linked active site. A previously described crystal structure of the inactivated enzyme shows a carbamate cross-link of Ser 64 and Lys 315. Structure-activity studies of the reported compounds suggest that they do not react at the enzyme active site in the same way as normal substrates. In particular, it appears that the initial acylation by these compounds does not involve the oxyanion hole, an unprecedented departure from known and presumed reactivity. Molecular modeling suggests that an alternative oxyanion hole may have been recruited, consisting of the side chain functional groups of Tyr 150 and Lys 315. Such an alternative mode of reaction may lead to the design of novel inhibitors.For decades now, β-lactams have been one of our most effective weapons against bacterial infections (1). These drugs, although still the first line of attack in many clinical situations, have been compromised to a considerable degree by bacterial resistance to them (2). Among various sources of resistance that have arisen in bacteria, the most generally troublesome is the production of β-lactamases. These enzymes very effectively catalyze the hydrolysis and thus destruction of β-lactams before they can reach their cellular targets (3).The threat posed by β-lactamases to the efficacy of β-lactam antibiotics has been tackled by pharmaceutical companies in several ways. One approach that has been quite successful to date is that of including a β-lactamase inhibitor with a β-lactam antibiotic in combination therapies. For many years now, such combinations, using the now-classical β-lactamase inhibitors clavulanic acid, sulbactam and tazobactam, have been used to advantage (4). Since these inhibitors are themselves β-lactams, however, it is perhaps not surprising to find that certain β-lactamase mutants are capable of hydrolyzing them quite effectively. Such mutants have †

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Pelto

Pratt

2008

Biochemistry

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ChemInform Abstract: Synthesis, Hydrolysis, and Evaluation of 3‐Acylamino‐3,4‐dihydro‐2‐oxo‐2H‐1,3‐benzoxazinecarboxylic Acids and Linear Azadepsipeptides as Potential Substrates/Inhibitors of β‐Lactam‐Recognizing Enzymes.

et al. 2002

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Aminophosphonic Acids and Aminobis(phosphonic acids) as Potential Inhibitors of Penicillin‐Binding Proteins

et al. 2008

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Aminophosphonic acids and aminobis(phosphonic acids) have been prepared by the alkylation of Schiff bases with methyl bromoacetate or ethyl acrylate. Other pathways, like the modified Pudovik reaction and Kabachnik–Fields reaction, have been considered for the synthesis of the α‐phosphonic bioisoster of aminocitrate. Partial or complete deprotection of the phosphonate ester have been realised by either acidic hydrolysis or by treatment with trimethylsilyl bromide. Evaluation against penicillin‐binding proteins has shown that our compounds are modest inhibitors of class A β‐lactamases, but have an interesting activity against R39 (D,D‐peptidase/carboxypeptidase). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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Synthesis, Hydrolysis, and Evaluation of 3-Acylamino-3,4-dihydro-2-oxo-2H-1,3-benzoxazinecarboxylic Acids and Linear Azadepsipeptides as Potential Substrates/Inhibitors of β-Lactam-Recognizing Enzymes

Cited by 14 publications

References 47 publications

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

ChemInform Abstract: Synthesis, Hydrolysis, and Evaluation of 3‐Acylamino‐3,4‐dihydro‐2‐oxo‐2H‐1,3‐benzoxazinecarboxylic Acids and Linear Azadepsipeptides as Potential Substrates/Inhibitors of β‐Lactam‐Recognizing Enzymes.

Aminophosphonic Acids and Aminobis(phosphonic acids) as Potential Inhibitors of Penicillin‐Binding Proteins

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