Structure-activity studies of the inhibition of serine β-lactamases by phosphonate monoesters

Li, Naixin; Rahil, Jubrail; Wright, Margaret E.; Pratt, Robertson

doi:10.1016/s0968-0896(97)00103-x

Cited by 27 publications

(26 citation statements)

References 28 publications

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“…The phosphonate species also prefer structure A (Table 2) and 10o has previously been interpreted as a mimic of a deacylation transition state (36,39). It might be noted in passing here that the thionophosphonate 10s (L ϭ p-nitrophenoxide) is a poorer inhibitor of the P99 ␤-lactamase than 10o (46). The comparison here is of second-order rate constants of irreversible inactivation, however, and presumably reflects the relative stabilities of the pentacoordinated intermediates.…”

Section: Structurementioning

confidence: 62%

The Oxyanion Hole in Serine β-Lactamase Catalysis: Interactions of Thiono Substrates with the Active Site

Curley

Pratt

2000

Bioorganic Chemistry

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Section: Structurementioning

confidence: 62%

The Oxyanion Hole in Serine β-Lactamase Catalysis: Interactions of Thiono Substrates with the Active Site

Curley

Pratt

2000

Bioorganic Chemistry

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“…Compounds 3 and 5 both have oxygen leaving groups but the conjugate acid pK a of the former is significantly lower than that of the former [4.2 vs 7.1 (29)]; the benzoate of 3 would therefore be expected to be the better leaving group and thus 3 the better phosphonylating agent. Previous studies have suggested that better leaving groups at phosphorus lead to better inhibitors (3,11). In accord with that idea, 3 inactivated all three ␤-lactamases more rapidly than did 5.…”

mentioning

confidence: 53%

“…The resulting mixture was stirred in an ice bath for 10 min and the precipitated product removed by filtration, washed with water, and dried in vacuo. The product, a colorless solid was characterized by its melting point (133-135ЊC), Attempts to prepare the N-phenylacetyl analog of 3 by the same method failed, probably because of the lability of this compound (9,11).…”

Section: Methodsmentioning

confidence: 99%

“…For reasons not understood at present, the R61 DD-peptidase is quite inert to phosphonates such as 5 (11). Nor is it acylated at a significant rate by non-specific acyl phosphonates such as benzoyl phenylphosphonate (1).…”

mentioning

confidence: 99%

“…The phosphonate 3 can be compared with 5, which has previously been studied in this laboratory. The phosphonate 5, and various analogs of it, inactivate ␤-lactamases by phosphonylation of the active site serine residue (3,11,17,28). Compounds 3 and 5 both have oxygen leaving groups but the conjugate acid pK a of the former is significantly lower than that of the former [4.2 vs 7.1 (29)]; the benzoate of 3 would therefore be expected to be the better leaving group and thus 3 the better phosphonylating agent.…”

mentioning

confidence: 99%

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

Morrison

Pratt

2001

Bioorganic Chemistry

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Noncovalent interaction energies in covalent complexes: TEM‐1 β‐lactamase and β‐lactams

2002

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The class A beta-lactamase TEM-1 is a key bacterial resistance enzyme against beta-lactam antibiotics, but little is known about the energetic bases for complementarity between TEM-1 and its inhibitors. Most inhibitors form a covalent adduct with the catalytic Ser70, making the measurement of equilibrium constants, and hence interaction energies, technically difficult. This study evaluates noncovalent interactions within covalent complexes by examining the differential stability of TEM-1 and its inhibitor adducts. The thermal denaturation of TEM-1 follows a two-state, reversible model with a melting temperature (T(m)) of 51.6C and a van't Hoff enthalpy of unfolding (DeltaH(VH)) of 146.2 kcal/mol at pH 7.0. The stability of the enzyme changes on forming an inhibitor adduct. As expected, some inhibitors stabilize TEM-1; transition-state analogues increase the T(m) by up to 3.7C (1.7 kcal/mol). Surprisingly, all beta-lactam covalent acyl--enzyme complexes tested destabilize TEM-1 significantly relative to the apo-enzyme. For instance, the clinically used inhibitor clavulanic acid and the beta-lactamase-resistant beta-lactams moxalactam and imipenem destabilize TEM-1 by over 2.6C (1.2 kcal/mol) in their covalent adducts. Based on the structure of the TEM-1/imipenem complex (Maveyraud et al., J Am Chem Soc 1998;120:9748--52), destabilization by moxalactam and imipenem is thought to be caused by a steric clash between the side-chain of Asn132 and the 6(7)-alpha group of these beta-lactams. To test this hypothesis, the mutant enzyme N132A was made. In contrast with wild-type, the covalent complexes between N132A and both imipenem and moxalactam stabilize the enzyme, consistent with the hypothesis. To investigate the structural bases of this dramatic change in stability, the structure of N132A/imipenem was determined by X-ray crystallography. In the complex with N132A, imipenem adopts a very different conformation from that observed in the wild-type complex, and the putative destabilizing interaction with residue 132 is relieved. Studies of several enzymes suggest that beta-lactams, and covalent inhibitors in general, can have either net favorable or net unfavorable noncovalent interaction energies within the covalent complex. In the case of TEM-1, such unfavorable interactions convert substrate analogues into very effective inhibitors.

show abstract

Structure-activity studies of the inhibition of serine β-lactamases by phosphonate monoesters

Cited by 27 publications

References 28 publications

The Oxyanion Hole in Serine β-Lactamase Catalysis: Interactions of Thiono Substrates with the Active Site

The Oxyanion Hole in Serine β-Lactamase Catalysis: Interactions of Thiono Substrates with the Active Site

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

Noncovalent interaction energies in covalent complexes: TEM‐1 β‐lactamase and β‐lactams

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