Studies on the mechanism of action of (5R)-(Z)-6-(1-methyl-1,2,3-triazol-4-ylmethylene)penem-3-carboxylic acid (BRL 427 15), a potent inhibitor of bacterial β-lactamase

Broom, Nigel J. P.; Farmer, T. H.; Osborne, Neal F.; Tyler, John W.

doi:10.1039/c39920001663

Cited by 30 publications

(32 citation statements)

References 8 publications

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“…However, the fact that the three class B enzymes studied did hydrolyze the compound suggests that it might be a substrate for most metallo-␤-lactamases and underlines the difficulties which might arise if these enzymes spread to a large number of pathogenic strains. In agreement with the results of Broom et al (3), the spectral properties of the product were identical to those of the dihydrothiazepine (Fig. 1B) obtained after sodium hydroxide hydrolysis.…”

Section: Discussionsupporting

confidence: 81%

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Kinetic study of interaction between BRL 42715, beta-lactamases, and D-alanyl-D-alanine peptidases

Matagne

Ledent

Monnaie

et al. 1995

Antimicrob Agents Chemother

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A detailed kinetic study of the interactions between BRL 42715, a ␤-lactamase-inhibiting penem, and various ␤-lactamases (EC 3.5.2.6) and D-alanyl-D-alanine peptidases (DD-peptidases, EC 3.4.16.4) is presented. The compound was a very efficient inactivator of all active-site serine ␤-lactamases but was hydrolyzed by the class B, Zn 2؉-containing enzymes, with very different k cat values. Inactivation of the Streptomyces sp. strain R61 extracellular DD-peptidase was not observed, and the Actinomadura sp. strain R39 DD-peptidase exhibited a low level of sensitivity to the compound.The production of ␤-lactamases by clinical isolates continues to be the main mechanism of bacterial resistance to ␤-lactam antibiotics. Whilst antibacterial therapy with ␤-lactamase-stable compounds has been partially successful in containing the problem, absolute stability has not been achieved with any one agent. Clinical experience has established that a second approach, using a specific ␤-lactamase inhibitor coadministered with a ␤-lactamase-labile antibiotic, offers a viable therapeutic option for combatting ␤-lactamase-mediated resistance. Although the three ␤-lactamase inhibitors in clinical use (clavulanic acid, sulbactam, and tazobactam) are effective inactivators of a wide range of ␤-lactamases, they do not inhibit all of the clinically important enzymes (4, 25).Of recent interest is the penem ␤-lactamase inhibitor, BRL 42715 (Fig. 1A), which is synthesized following a stereocontrolled reaction sequence starting from the chiral synthon, 6-aminopenicillanic acid (23). BRL 42715 alone possesses no appreciable antibacterial activity (MIC, 16 to 64 g/ml) except against the methicillin-sensitive staphylococci (MIC, 1 g/ml). In cell-free ␤-lactamase assays, this inhibitor shows intrinsic activity which is superior to that of clavulanic acid, sulbactam, or tazobactam. Significantly, it is able to inactivate the plasmidmediated OXA-1 ␤-lactamase and the chromosomally mediated enzymes of Enterobacter, Citrobacter, Pseudomonas, Serratia, and Morganella species, against which the other inhibitors show poor activity. Its potent inhibitory activity is reflected in its ability to potentiate the antibacterial properties of a wide range of ␤-lactamase-susceptible ␤-lactam antibiotics, including third generation cephalosporins, at very low concentrations. Higher concentrations (Ϸ1 g/ml) are required, however, against those strains producing elevated levels of class C ␤-lactamases (5, 7). The BRL 42715 diffusion rate through the outer membranes of gram-negative bacteria is similar to those of sulbactam and tazobactam but lower than that of clavulanic acid (11). However, thanks to its superior intrinsic activity, it remains the most active inhibitor against whole cells. In contrast to other penems, it is not readily hydrolyzed by the renal dehydropeptidase (6).The kinetics of inhibition of ␤-lactamases of Staphylococcus aureus NCTC 11561 (class A), Escherichia coli JT4 (TEM-1, class A), and Enterobacter cloacae P99 (class C) by BRL 42715 has been...

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Section: Discussionsupporting

confidence: 81%

“…By contrast, BRL 42715 was an extremely efficient inactivator of all tested active-site serine ␤-lactamases. Table 3 summarizes our results and those obtained earlier (3,12), with which they were in excellent agreement. On the basis of the model (with k Ϫ4 Ϸ 0), these enzymes can be divided into two groups.…”

Section: Discussionsupporting

confidence: 78%

Kinetic study of interaction between BRL 42715, beta-lactamases, and D-alanyl-D-alanine peptidases

Matagne

Ledent

Monnaie

et al. 1995

Antimicrob Agents Chemother

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“…Previous studies of compound BRL 42715 (see Fig. 1), which has a structure similar to penem 1, showed that its reaction with a base (sodium methoxide in methanol) results in the formation of a seven-membered thiazepine with chromophores at 253 and 370 nm (40), which is consistent with the peaks in UVD spectroscopy of OXA-1. In addition, the NMR studies by Bethel et al (20) also support the conclusion that a similar intermediate, the 1,4-thiazepine derivative, is formed during the reaction between penem 1 and OXA-1.…”

Section: Spectroscopic Evidence For Different Reaction Schemes In Oxasupporting

confidence: 73%

The Different Inhibition Mechanisms of OXA-1 and OXA-24 β-Lactamases Are Determined by the Stability of Active Site Carboxylated Lysine

Che

Bethel

Pusztai-Carey

et al. 2014

Journal of Biological Chemistry

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Background: OXA-1 and OXA-24 are class D ␤-lactamases that resist clinically used inhibitors. Results: Spectroscopic methods and kinetic measurements show that penem drug candidates are good inhibitors of OXA-1 but are rapidly hydrolyzed by OXA-24. Conclusion: An active site water in OXA-24 aids the reversible carboxylation of Lys-84, enabling many reaction cycles. Significance: Understanding the mechanism of class D ␤-lactamases is vital for drug development.

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“…Initial studies to elucidate the BRL 42715 inactivation product using UV difference spectroscopy for both enzyme-and basecatalyzed hydrolysis of the methylidene penem suggested the presence of a dihydrothiazepine rearrangement product (46,250). Accordingly, mass spectrometry studies demonstrated that the methylidene penem inhibition pathway does not involve fragmentation in the active site (119,250,406).…”

Section: Penemsmentioning

confidence: 99%

“…However, some class A enzymes, such as the ␤-lactamases from Staphylococcus albus (Staphylococcus epidermidis) and K. pneumoniae K1, exhibit more complex kinetics (46,250). A branched pathway leads to an acyl-enzyme hydrolysis product, which also rapidly rearranges to the dihydrothiazepine species.…”

Section: Penemsmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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SUMMARYSince the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of seriousEnterobacteriaceaeand penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.

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Studies on the mechanism of action of (5R)-(Z)-6-(1-methyl-1,2,3-triazol-4-ylmethylene)penem-3-carboxylic acid (BRL 427 15), a potent inhibitor of bacterial β-lactamase

Cited by 30 publications

References 8 publications

Kinetic study of interaction between BRL 42715, beta-lactamases, and D-alanyl-D-alanine peptidases

Kinetic study of interaction between BRL 42715, beta-lactamases, and D-alanyl-D-alanine peptidases

The Different Inhibition Mechanisms of OXA-1 and OXA-24 β-Lactamases Are Determined by the Stability of Active Site Carboxylated Lysine

Three Decades of β-Lactamase Inhibitors

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