Inverse Acyl Phosph(on)ates: Substrates or Inhibitors of β-Lactam-Recognizing Enzymes?

Morrison, Michael J.; Li, Naixin; Pratt, Robertson

doi:10.1006/bioo.2001.1218

Cited by 10 publications

(3 citation statements)

References 31 publications

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“…It had been proposed by Pratt and colleagues that phosphate-based compounds could serve as effective inhibitors of β-lactamases [25,26,27,28]. They first demonstrated that a phosphonate monoester inhibited the activity of the class C β-lactamase P99 towards benzylpenicillin [25].…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

Moural

White

Choy

et al. 2019

IJMS

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Mycobacterium tuberculosis, the pathogen responsible for tuberculosis (TB), is the leading cause of death from infectious disease worldwide. The class A serine β-lactamase BlaC confers Mycobacterium tuberculosis resistance to conventional β-lactam antibiotics. As the primary mechanism of bacterial resistance to β-lactam antibiotics, the expression of a β-lactamase by Mycobacterium tuberculosis results in hydrolysis of the β-lactam ring and deactivation of these antibiotics. In this study, we conducted protein X-ray crystallographic analysis of the inactivation of BlaC, upon exposure to the inhibitor bis(benzoyl) phosphate. Crystal structure data confirms that serine β-lactamase is phosphorylated at the catalytic serine residue (Ser-70) by this phosphate-based inactivator. This new crystallographic evidence suggests a mechanism for phosphorylation of BlaC inhibition by bis(benzoyl) phosphate over acylation. Additionally, we confirmed that bis(benzoyl) phosphate inactivated BlaC in a time-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

Moural

White

Choy

et al. 2019

IJMS

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“…The acyl phosphonate 18 was an irreversible inhibitor of β-lactamases, probably by phosphonylation of the serine ( Figure 9 ), but was found to be a poor inhibitor of R61 with k 2 /K- value of 5 × 10 −3 M −1 s −1 . A very slow turnover of this molecule by R61 was observed ( K m = 0.21 mM, k ca t = 3.5 × 10 −4 s −1 ) meaning that an acyl-enzyme is formed or that the phosphoronyl enzyme is unstable [ 79 ].…”

Section: Non-beta-lactamsmentioning

confidence: 99%

Development of New Drugs for an Old Target — The Penicillin Binding Proteins

et al. 2012

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The widespread use of β-lactam antibiotics has led to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to β-lactams by two main mechanisms: the production of β-lactamases, sometimes accompanied by a decrease of outer membrane permeability, and the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs). PBPs remain attractive targets for developing new antibiotic agents because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique to bacteria, and lies outside the cytoplasmic membrane. Here we summarize the “current state of the art” of non-β-lactam inhibitors of PBPs, which have being developed in an attempt to counter the emergence of β-lactam resistance. These molecules are not susceptible to hydrolysis by β-lactamases and thus present a real alternative to β-lactams. We present transition state analogs such as boronic acids, which can covalently bind to the active serine residue in the catalytic site. Molecules containing ring structures different from the β-lactam-ring like lactivicin are able to acylate the active serine residue. High throughput screening methods, in combination with virtual screening methods and structure based design, have allowed the development of new molecules. Some of these novel inhibitors are active against major pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and thus open avenues new for the discovery of novel antibiotics.

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“…Aroyl phosphates, 1 , have proven to be very effective inhibitors of serine β-lactamases − . The phosphate leaving group appears to interact with polar residues in such a way as to enhance active site acylation by both specific amidoacyl groups and nonclassical aroyl groups − . Acylation by the latter leads to hydrolytically refractive acyl-enzymes and thus to significant inhibition (Scheme ).…”

mentioning

confidence: 99%

Intramolecular Cooperativity in the Reaction of Diacyl Phosphates with Serine β-Lactamases

Majumdar

Pratt

2009

Biochemistry

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Asymmetric diaroyl phosphates (ArCOOPO2−OCOAr′, where Ar = Ph, Ar′ = 4-biphenyl, 2-benzothiophenyl and 2-benzofuranyl), have been prepared, evaluated as serine (classes A, C, D) β-lactamase inhibitors, and compared with respect to the latter with their symmetric “parents”, where Ar = Ar′. The asymmetric compounds, in general, were found to react with the β-lactamases in two modes, corresponding to different orientations with respect to the active site, whereby either of the two aroyl groups may acylate the enzyme to form two different inert acyl-enzymes, E-COAr and E-COAr′. In all cases, the asymmetric compounds, in one orientation, react more rapidly with the enzymes tested than one symmetrical “parent” but not both. From comparisons of activation free energy differences, it was found that the changes in free energy on changing from one aryl group to another, in either the acyl group or the leaving group, were not additive, i.e. that the effect of changing one aroyl group to another depended on the leaving group and vice versa. Thus, intramolecular cooperativity between the aroyl groups must exist, arising either from direct interaction between them or from protein-mediated interaction, or from a combination of both. Such cooperativity brings fresh opportunities and challenges to the search for novel ß-lactamase inhibitors.

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Inverse Acyl Phosph(on)ates: Substrates or Inhibitors of β-Lactam-Recognizing Enzymes?

Cited by 10 publications

References 31 publications

Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

Development of New Drugs for an Old Target — The Penicillin Binding Proteins

Intramolecular Cooperativity in the Reaction of Diacyl Phosphates with Serine β-Lactamases

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