In vitro activity of AVE1330A, an innovative broad-spectrum non- -lactam  -lactamase inhibitor

Bonnefoy, Alain

doi:10.1093/jac/dkh358

Cited by 162 publications

(121 citation statements)

References 19 publications

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“…The measured off-rate for avibactam suggested that slow deacylation through hydrolysis or reversibility was occurring, and it is in contrast to previously reported extremely long t 1/2 values of >1 or >7 d for avibactam inhibition of TEM-1 (15,16). We investigated the methods used in these earlier studies and concluded that these data resulted from measuring initial rates of enzyme activity within seconds after dilution of a 1 μM acylenzyme (EI*) complex.…”

Section: Resultsmentioning

confidence: 93%

Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor

Ehmann

Jahić

Ross

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

449

450

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Avibactam is a β-lactamase inhibitor that is in clinical development, combined with β-lactam partners, for the treatment of bacterial infections comprising Gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a β-lactam core but maintains the capacity to covalently acylate its β-lactamase targets. Using the TEM-1 enzyme, we characterized avibactam inhibition by measuring the on-rate for acylation and the offrate for deacylation. The deacylation off-rate was 0.045 min −1 , which allowed investigation of the deacylation route from TEM-1. Using NMR and MS, we showed that deacylation proceeds through regeneration of intact avibactam and not hydrolysis. Other than TEM-1, four additional clinically relevant β-lactamases were shown to release intact avibactam after being acylated. We showed that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.antibacterial | drug discovery | enzymology T here is an urgent need for new antibacterial agents that are active against drug-resistant bacteria. In particular, some Gram-negative pathogens have accumulated enough resistance mechanisms to render them virtually untreatable by modern antibacterial chemotherapy (1, 2). A mainstay for treatment of Gram-negative infections is the β-lactam classes of drugs. The most common form of resistance to β-lactam antibiotics is the expression of various β-lactamase enzymes capable of hydrolyzing the β-lactam ring of β-lactam drugs, rendering them ineffective. As new β-lactams have been introduced into clinical use, a changing landscape of β-lactamases has been selected and disseminated. Presently, over 1,000 β-lactamases have been documented comprising several structural classes and a wide range of substrate promiscuities and catalytic efficiencies (3, 4).In efforts to restore the efficacy of β-lactam antibiotics, β-lactamases have also been targeted with a variety of inhibitors (5, 6). The three inhibitors approved for clinical use are clavulanic acid, tazobactam, and sulbactam, all of which contain a β-lactam core. A challenge for the development of broad-spectrum β-lactamase inhibitors is the mechanistic diversity in β-lactamase enzymes, with the largest distinction being between the enzyme classes that use a serine residue as the nucleophilic species and the metallo-β-lactamases, which directly activate water for hydrolysis (7). A shared mechanistic feature of the marketed β-lactam-based inhibitors is their reaction with the serine enzymes to form a covalent acylenzyme intermediate. On ring opening, the acyl-enzyme intermediate can undergo additional rearrangements or be released through hydrolysis to regenerate the active β-lactamase enzyme (8). Originally designed to combat class A serine β-lactamase enzymes such as TEM-1, the clinical use of β-lactam-based inhibitors has been diminished by the emergence of enzymes against which they are ineffective. Despite intense investigation by pharmaceutical companies, no new β-lactamas...

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Section: Resultsmentioning

confidence: 93%

Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor

Ehmann

Jahić

Ross

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

449

450

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“…A remarkable property of NXL104 is the prolonged deacylation rate. The 50% enzyme recovery time point was 7 days for both TEM-1 and P99 (compared to 7 min for TEM-1 and clavulanate and 290 min for P99 and tazobactam), suggesting the presence of a very stable and long-lived intermediate species (31). The formation of a covalent complex has been supported by an ESI-MS study of TEM-1 and NXL104 (391).…”

Section: Non-␤-lactam Inhibitorsmentioning

confidence: 85%

“…1, compound 26) is a bridged diazabicyclo[3.2.1]octanone non-␤-lactam inhibitor with very promising activity against class A, C, and D ␤-lactamases (31,116,240,390). The majority of the published work on NXL104 describes MIC testing, although IC 50 s of 8, 38, and 80 nM have been reported for class A TEM-1 and KPC-2 and class C P99 enzymes, respectively (31,390). A remarkable property of NXL104 is the prolonged deacylation rate.…”

Section: Non-␤-lactam Inhibitorsmentioning

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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“…It displays a broad spectrum of inhibitory activity against both class A and class C ␤-lactamases, including Klebsiella pneumoniae carbapenemase (KPC) enzymes (2), the AmpC ␤-lactamase of Pseudomonas aeruginosa (3), and extendedspectrum ␤-lactamases such as TEM, SHV, and CTX-M variants (4,5). In studies with isolated enzymes, avibactam inactivates ␤-lactamases at low 50% inhibitory concentrations and with low turnover numbers (6,7).…”

mentioning

confidence: 99%

“…It also inhibits some class D ␤-lactamases, OXA-48, for example (8). Avibactam has little intrinsic antibacterial activity but efficiently protects ␤-lactams from ␤-lactamase-catalyzed hydrolysis in a range of members of the family Enterobacteriaceae and in P. aeruginosa (3)(4)(5)9). That a combination of ceftazidime and avibactam protects against bacterial infections by ␤-lactamase-producing bacteria has been demonstrated in animal models (10,11), and two successful phase 2 human studies have been reported (12,13).…”

mentioning

confidence: 99%

Activities of Ceftazidime and Avibactam against β-Lactamase-Producing Enterobacteriaceae in a Hollow-Fiber Pharmacodynamic Model

Coleman¹,

Levasseur²,

Girard³

et al. 2014

Antimicrob Agents Chemother

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Avibactam is a novel non-␤-lactam ␤-lactamase inhibitor that is currently undergoing phase 3 clinical trials in combination with ceftazidime. Ceftazidime is hydrolyzed by a broad range of ␤-lactamases, but avibactam is able to inhibit the majority of these enzymes. The studies described here attempt to provide insight into the amount of avibactam required to suppress bacterial growth in an environment where the concentrations of both agents are varying as they would when administered to humans. Following the simulation of a single intravenous dose of the drug, ceftazidime alone had no effect on any test organism, but a ceftazidime-avibactam combination resulted in rapid killing of all of the strains, with growth suppressed for the 8 h of the study. For seven of eight strains, this was achieved with a 1-g-250-mg profile, but a 2-g-500-mg profile was necessary to completely suppress a high-level-AmpC-producing isolate. When ceftazidime was infused continuously for 24 h with a single bolus dose of avibactam, rapid killing of all of the strains was again observed, with growth suppressed for 10 to >24 h. Regrowth appeared to commence once the avibactam concentration dropped below a critical concentration of approximately 0.3 g/ml. In a third series of studies, ceftazidime was administered every 8 h for 24 h with avibactam administered at fixed concentrations for short periods during each ceftazidime dose profile. Simulating a 1-g dose of ceftazidime, an avibactam pulse of >0.25 and <0.5 g/ml was required to suppress growth for 24 h. A vibactam, formerly NXL104 or AVE1330A, is the first of a new class of non-␤-lactam ␤-lactamase inhibitors, referred to as diazabicyclooctanes (1). It displays a broad spectrum of inhibitory activity against both class A and class C ␤-lactamases, including Klebsiella pneumoniae carbapenemase (KPC) enzymes (2), the AmpC ␤-lactamase of Pseudomonas aeruginosa (3), and extendedspectrum ␤-lactamases such as TEM, SHV, and CTX-M variants (4, 5). In studies with isolated enzymes, avibactam inactivates ␤-lactamases at low 50% inhibitory concentrations and with low turnover numbers (6, 7). It also inhibits some class D ␤-lactamases, OXA-48, for example (8). Avibactam has little intrinsic antibacterial activity but efficiently protects ␤-lactams from ␤-lactamase-catalyzed hydrolysis in a range of members of the family Enterobacteriaceae and in P. aeruginosa (3-5, 9). That a combination of ceftazidime and avibactam protects against bacterial infections by ␤-lactamase-producing bacteria has been demonstrated in animal models (10, 11), and two successful phase 2 human studies have been reported (12,13).Like the pharmacodynamic (PD) indices of other cephalosporins (14) and ␤-lactams generally (15), that of ceftazidime is the time during which its free (non-protein-bound) concentration exceeds the MIC for the infecting pathogen (fTϾMIC) (14-19). However, little is known about ␤-lactam-␤-lactamase-inhibitor pharmacokinetic (PK)-PD relationships (20)(21)(22), which is a prerequisite for the optimum design...

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In vitro activity of AVE1330A, an innovative broad-spectrum non- -lactam -lactamase inhibitor

Abstract: The combination of ceftazidime with AVE1330A exhibited broad-spectrum activity against Ambler class A- and class C-producing Enterobacteriaceae.

Cited by 162 publications

References 19 publications

Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor

Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor

Three Decades of β-Lactamase Inhibitors

Activities of Ceftazidime and Avibactam against β-Lactamase-Producing Enterobacteriaceae in a Hollow-Fiber Pharmacodynamic Model

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