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Avibactam Is a Covalent, Reversible, Non–Β-Lactam Β-Lactamase Inhibitor

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Avibactam Is a Covalent, Reversible, Non–Β-Lactam Β-Lactamase Inhibitor Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor David E. Ehmann1, Haris Jahic´, Philip L. Ross, Rong-Fang Gu, Jun Hu, Gunther Kern, Grant K. Walkup, and Stewart L. Fisher Infection Innovative Medicines Unit, AstraZeneca Research & Development Boston, Waltham, MA 02451 Edited by Vern L. Schramm, Albert Einstein College of Medicine, Bronx, NY, and approved June 5, 2012 (received for review March 26, 2012) Avibactam is a β-lactamase inhibitor that is in clinical develop- Gram-negative organisms (http://clinicaltrials.gov). A design ment, combined with β-lactam partners, for the treatment of bac- strategy for β-lactamase inhibitors has been to focus on scaffolds terial infections comprising Gram-negative organisms. Avibactam that maintain the capacity to rapidly acylate a wide range of is a structural class of inhibitor that does not contain a β-lactam β-lactamases while minimizing the liability of hydrolysis. Avi- core but maintains the capacity to covalently acylate its β-lacta- bactam has been described as possessing these desirable prop- mase targets. Using the TEM-1 enzyme, we characterized avibac- erties (9), but the molecular understanding of how it inhibits its tam inhibition by measuring the on-rate for acylation and the off- targets is not well-understood. rate for deacylation. The deacylation off-rate was 0.045 min−1, In this work, the detailed enzymatic mechanism of inhibition for which allowed investigation of the deacylation route from TEM-1. avibactam against the β-lactamase TEM-1 is described. Investi- Using NMR and MS, we showed that deacylation proceeds through gation of onset of and recovery from TEM-1 inhibition, coupled regeneration of intact avibactam and not hydrolysis. Other than with biophysical measurements of the enzyme–inhibitor complex, TEM-1, four additional clinically relevant β-lactamases were shown leads us to propose a model for covalent β-lactamase inhibition to release intact avibactam after being acylated. We showed that that is reversible but not susceptible to hydrolysis. Profiling of avibactam is a covalent, slowly reversible inhibitor, which is a unique additional clinically important class A and C β-lactamases sug- mechanism of inhibition among β-lactamase inhibitors. gests that this highly unusual reversible acylation and deacylation mechanism is a general mechanism of inhibition for avibactam. antibacterial | drug discovery | enzymology Results β here is an urgent need for new antibacterial agents that are Onset of Acylation. The onset of inhibition of TEM-1 -lactamase active against drug-resistant bacteria. In particular, some by avibactam was investigated using conventional and stopped- T fl fl Gram-negative pathogens have accumulated enough resistance ow spectroscopy. Without stopped- ow spectroscopy, the ad- ∼ mechanisms to render them virtually untreatable by modern dition of enzyme resulted in a time lag of 3 s in our apparatus antibacterial chemotherapy (1, 2). A mainstay for treatment of and allowed investigation of avibactam concentrations up to μ fi Gram-negative infections is the β-lactam classes of drugs. The 2.5 M. Under these conditions, the observed pseudo rst-order most common form of resistance to β-lactam antibiotics is the rate constant for formation of inhibited enzyme, kobs, was not expression of various β-lactamase enzymes capable of hydrolyz- saturable with respect to the concentration of avibactam. Stop- fl ing the β-lactam ring of β-lactam drugs, rendering them in- ped- ow equipment allowed interrogation of shorter time regi- effective. As new β-lactams have been introduced into clinical mens from 250 ms to 7 s and higher avibactam concentrations μ use, a changing landscape of β-lactamases has been selected and from 8 to 50 M. The kobs values from both studies overlaid with disseminated. Presently, over 1,000 β-lactamases have been each other and remained linear at the highest avibactam con- documented comprising several structural classes and a wide centration (Fig. 2). Although this linear relationship is required range of substrate promiscuities and catalytic efficiencies (3, 4). of a one-step inhibition mechanism, it is also consistent with a BIOCHEMISTRY In efforts to restore the efficacy of β-lactam antibiotics, β-lac- two-step binding and acylation process, where the initial binding β tamases have also been targeted with a variety of inhibitors (5, 6). constant is very weak (10). Covalent -lactamase inhibitors fol- The three inhibitors approved for clinical use are clavulanic acid, low a two-step binding and acylation reaction, and based on this tazobactam, and sulbactam, all of which contain a β-lactam core. A precedent, avibactam inhibition was modeled to a two-step challenge for the development of broad-spectrum β-lactamase in- mechanism as described in Materials and Methods. Fitting the plot of kobs vs. inhibitor concentration to an equation discussed hibitors is the mechanistic diversity in β-lactamase enzymes, with − − in Materials and Methods yielded a slope of 1.6 × 105 M 1s 1 the largest distinction being between the enzyme classes that use a 5 −1 −1 β (±0.1 × 10 M s at 95% confidence interval). For a two-step serine residue as the nucleophilic species and the metallo- -lac- fi tamases, which directly activate water for hydrolysis (7). A shared mechanism with a weak af nity for the initial encounter complex, β – the slope value determined in this manner is the second-order mechanistic feature of the marketed -lactam based inhibitors β is their reaction with the serine enzymes to form a covalent acyl- rate constant for -lactamase acylation. The contributing terms enzyme intermediate. On ring opening, the acyl-enzyme inter- for the noncovalent Ki and the ring-opening chemical step k2 mediate can undergo additional rearrangements or be released cannot be determined precisely (11). 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 Author contributions: D.E.E., H.J., P.L.R., R.-F.G., J.H., G.K., G.K.W., and S.L.F. designed research; H.J., P.L.R., R.-F.G., J.H., G.K., and G.K.W. performed research; H.J., P.L.R., R.-F.G., been diminished by the emergence of enzymes against which they J.H., G.K., and G.K.W. analyzed data; and D.E.E. wrote the paper. are ineffective. Despite intense investigation by pharmaceutical Conflict of interest statement: All authors are present or past employees of AstraZeneca, companies, no new β-lactamase inhibitor has reached the market as stated in the affiliations, and potentially own stock and/or hold stock options in in over 19 years. the company. Avibactam (Fig. 1) is a member of a class of inhibitors called This article is a PNAS Direct Submission. the diazabicyclooctanes (DBOs) (9), and it is currently entering 1To whom correspondence should be addressed. E-mail: [email protected]. phases II and III clinical trials combined with ceftaroline and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ceftazidime for the treatment of serious infections caused by 1073/pnas.1205073109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1205073109 PNAS | July 17, 2012 | vol. 109 | no. 29 | 11663–11668 Downloaded by guest on October 2, 2021 Fig. 1. Structures of β-lactamase inhibitors used in this study. Off-Rate of Deacylation. The experiments investigating the onset of observed. By following the return of activity in a continuous avibactam inhibition revealed that the off-rate for return of en- manner for 1 h at a much lower EI* concentration (25 pM as in zyme activity was much slower than the time regimen for onset of Fig. 2), the deacylation from TEM-1 can be measured. acylation. Therefore, a separate experiment was performed to measure the deacylation off-rate. The most common routes of Lack of Hydrolysis or Rearrangement. The recovery of enzyme ac- deacylation of β-lactamase inhibitors are through hydrolysis, tivity on dilution of the acylated enzyme led to experiments chemical rearrangement, or a combination of these paths (8). Off- designed to identify the deacylation routes involved. Avibactam rates for deacylation from TEM-1 were measured using a jump has been assumed to covalently acylate its β-lactamase target dilution method (12) comparing avibactam with clavulanic acid based on acyl-enzyme adducts seen in electrospray ionization MS and tazobactam. Avibactam displayed a slow return of activity (16). To eliminate the possibility of a tight noncovalent interaction, − with an off-rate of 0.045 ± 0.022 min 1, which converts to a resi- the acylated TEM-1 was subjected to strong denaturing conditions followed by MS. The retention of the acyl-enzyme adduct (Fig. S2) dence time half-life (t1/2)of16± 8 min (Fig. 3). In contrast, TEM- 1 with clavulanic acid displayed a partial return of activity, which under these conditions supports the covalent nature of this linkage. > is attributed to rearrangement from the acylated enzyme form to The observation that enzyme inhibition was maintained for 24 h μ additional irreversible acyl-enzyme species (13). TEM-1 in- at 1 M acyl-enzyme (Fig. S1) suggested that the carbamoyl acyl- hibition by tazobactam follows a branched deacylation pathway enzyme intermediate is stable to hydrolysis. This suggestion was fi 1 that favors hydrolysis over rearrangement (14), which in the off- con rmed by H NMR spectroscopy. As opposed to tazobactam, rate assay, manifested as a rapid return to nearly full activity. which was hydrolyzed by TEM-1 (Fig. 4A), avibactam remained The measured off-rate for avibactam suggested that slow intact after 24 h of incubation with a high concentration of TEM-1 deacylation through hydrolysis or reversibility was occurring, and (Fig.
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