Inhibition of β-Lactamases by Monocyclic Acyl Phosph(on)ates

Kaur, Kamaljit; Adediran, S. A.; Lan, Martin J. K.; Pratt, Robertson

doi:10.1021/bi020602q

Cited by 27 publications

(20 citation statements)

References 36 publications

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“…There are currently several different classes of potentially active ␤-lactamase inhibitors under investigation, including the oxapenems, penicillin derivatives, cyclic acyl phosphonates, and cephalosporin-derived compounds (3,9,11,14,18,21,26).…”

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confidence: 99%

In Vitro and In Vivo Activities of Novel 6-Methylidene Penems as β-Lactamase Inhibitors

Weiss¹,

Petersen²,

Murphy³

et al. 2004

Antimicrob Agents Chemother

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Novel penem molecules with heterocycle substitutions at the 6 position via a methylidene linkage were investigated for their activities and efficacy as ␤-lactamase inhibitors. The concentrations of these molecules that resulted in 50% inhibition of enzyme activity were 0.4 to 3.1 nM for the TEM-1 enzyme, 7.8 to 72 nM for Imi-1, 1.5 to 4.8 nM for AmpC, and 14 to 260 nM for a CcrA metalloenzyme. All the inhibitors were more stable than imipenem against hydrolysis by hog and human dehydropeptidases. Piperacillin was combined with a constant 4-g/ml concentration of each inhibitor for MIC determinations. The combinations reduced piperacillin MICs by 2-to 32-fold for extended-spectrum ␤-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae strains. The MICs for piperacillin-resistant (MIC of piperacillin, >64 g/ml) strains of Enterobacter spp., Citrobacter spp., and Serratia spp. were reduced to the level of susceptibility (MIC of piperacillin, <16 g/ml) when the drug was combined with 4, 2, or 1 g of these penem inhibitors/ml. Protection against acute lethal bacterial infections with class A and C ␤-lactamase-and ESBL-producing organisms in mice was also demonstrated with piperacillin plus inhibitor. Median effective doses were reduced by approximately two-to eightfold compared to those of piperacillin alone when the drug was combined with the various inhibitors at a 4:1 ratio. Pharmacokinetic analysis after intravenous administration of the various inhibitors showed mean residence times of 0.1 to 0.5 h, clearance rates of 15 to 81 ml/min/kg, and volumes of distribution between 0.4 and 2.5 liters/kg. The novel methylidene penem molecules inhibit both class A and class C enzymes and warrant further investigation for potential as therapeutic agents when used in combination with a ␤-lactam antibiotic.

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confidence: 99%

In Vitro and In Vivo Activities of Novel 6-Methylidene Penems as β-Lactamase Inhibitors

Weiss¹,

Petersen²,

Murphy³

et al. 2004

Antimicrob Agents Chemother

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confidence: 62%

“…Of the cyclic acyl phosph(on)ates 6 to 9, the 4-phenyl phosphate 7 and its phosphonate analogue 9 are most effective. It is interesting to note that this pattern of activity closely mimics that against the class A TEM ␤-lactamase (4,9,17,18).The reactivity of dibenzoyl phosphate, 4, with the OXA-1 ␤-lactamase is quite striking, and even without structural optimization, it is comparable to that of clavulanic acid (k i ϭ 2.2 ϫ 10 5 s Ϫ1 M Ϫ1 under the same conditions). The inactivation by 4 was found to be slowly reversible (5, 7), corresponding to a directly measured turnover number (k cat ) of (4.9 Ϯ 0.9) ϫ10 Ϫ3 s Ϫ1 (the half-life of the EI complex was thus 2.4 min; cf.…”

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confidence: 65%

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Inhibition of Class D β-Lactamases by Acyl Phosphates and Phosphonates

Adediran

Nukaga

Baurin

et al. 2005

Antimicrob Agents Chemother

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The susceptibility of typical class D ␤-lactamases to inhibition by acyl phosph(on)ates has been determined. To a large degree, these class D enzymes behaved very similarly to the class A TEM ␤-lactamase towards these reagents. Dibenzoyl phosphate stood out in both cases as a lead compound towards a new class of effective inhibitors.The resistance of bacteria to ␤-lactam antibiotics is to a large extent due to ␤-lactamases (14). There is a wide range of ␤-lactamases, although from a structural standpoint, they can be divided into four classes, A, B, C, and D (11). Each class contains many variants of widely differing substrate specificities and thus clinical importance. Of the canonical four classes, it is perhaps class D that at present is least well studied at the molecular level.The class D ␤-lactamases, also generally known as oxacillinases because of their general specificity for oxacillin and its derivatives, represent a diverse class of enzymes (1) that hydrolyze a broad spectrum of substrates (2). Like class A and C ␤-lactamases, the class D enzymes are serine hydrolases, catalyzing substrate hydrolysis by way of a covalent acyl-enzyme (acyl-serine) intermediate and thus by a double-displacement mechanism. Structural studies indicate that the class D ␤-lactamases are more closely related to class A than to class C, although there are distinct differences in active-site structures and thus, presumably, in chemical mechanisms (20). Although class D ␤-lactamases are clinically significant, there are no specific inhibitors known for them other than certain inhibitory ␤-lactams (8, 12) and a series of anthraquinone dyes (15). The classical mechanism-based inhibitors of class A ␤-lactamases are not generally effective against class D (16). A variety of phosph(on)ates have been found to be covalent inhibitors of class A and class C ␤-lactamases (4,5,9,(17)(18)(19). This paper describes the screening of a panel of these compounds, 1 to 9, against the class D OXA-1 ␤-lactamase. This enzyme is representative of one subclass of the D enzymes (1) and is clinically important in its own right; a crystal structure is also available (20). The more effective compounds of 1 to 9 (Fig. 1) were also tested against the OXA-10 enzyme, a representative of another major class D subgroup (1).The OXA-1 and OXA-10 ␤-lactamases were prepared and purified as described previously (8,20). The various phosph(on)ates were available from previous studies (4, 5, 9, 17-19). The phosphates 2 and 4 to 8 and the phosphonates 1, 3, and 9 were all irreversible or slowly reversible inhibitors of the OXA ␤-lactamases, and the inactivation step could be described simply by scheme 1 as follows:where E is the free enzyme and I is the inhibitor. Second-order rate constants of inactivation were obtained from measurements of the loss of enzyme activity as a function of time (18,19). All kinetics studies were performed at 25°C in a buffer at pH 7.5 containing 20 mM MOPS (3-morpholinopropanesulfonic acid) and 50 mM sodium bicarbonate (3). The enzyme conc...

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“…Th is compound also bound TEM-2 and P99 β-lactamases non-covalently. Similar to other novel inhibitors, it is eff ective against class A and class C enzymes [27].…”

Section: -Phenyl Cyclic Phosphatementioning

confidence: 98%