<i>O</i>-Aryloxycarbonyl Hydroxamates:  New β-Lactamase Inhibitors That Cross-Link the Active Site

Wyrembak, Pauline N.; Babaoglu, Kerim; Pelto, Ryan B.; Shoichet, Brian K.; Pratt, Robertson

doi:10.1021/ja072370u

Cited by 36 publications

(66 citation statements)

References 14 publications

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“…12) (PDB 2P9V) (450). TEM-2 and OXA-1 ␤-lactamases were also inhibited by O-aryloxycarbonyl hydroxamates, and the MBL GIM-1 was inhibited by a "reverse" hydroxamate (hydroxylamino replacing hydroxylamine) conjugated to a cephalosporin nucleus (131,330).…”

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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Section: Non-␤-lactam Inhibitorsmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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“…RPX7009 is undergoing Phase I trials in combination with a carbapenem, biapenem. These recent successes demonstrate that novel, non-β-lactam compounds can be employed clinically to inhibit β-lactamases in resistant bacteria [26–29]. …”

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confidence: 99%

Fragment-Based Inhibitor Discovery Against β-Lactamase

2014

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The production of β-lactamase is one of the primary resistance mechanisms used by Gram-negative bacterial pathogens to counter β-lactam antibiotics, such as penicillins, cephalosporins and carbapenems. There is an urgent need to develop novel β-lactamase inhibitors in response to ever evolving β-lactamases possessing an expanded spectrum of β-lactam hydrolyzing activity. Whereas traditional high-throughput screening has proven ineffective against serine β-lactamases, fragment-based approaches have been successfully employed to identify novel chemical matter, which in turn has revealed much about the specific molecular interactions possible in the active site of serine and metallo β-lactamases. In this review, we summarize recent progress in the field, particularly: the identification of novel inhibitor chemotypes through fragment-based screening; the use of fragment-protein structures to understand key features of binding hot spots and inform the design of improved leads; lessons learned and new prospects for β-lactamase inhibitor development using fragment-based approaches.

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“…Methyl 4-nitrophenylcarbonate (11) was prepared from reaction of 4-nitrophenyl chloroformate with methanol in the presence of triethylamine and recrystallized from an ethyl acetate/hexane mixture (7:3). Ethyl 4-nitrophenyl carbonate (13) was prepared from reaction of 4-nitrophenol with ethyl choroformate in the presence of aqueous sodium hydroxide and recrystallized from ethanol [10].…”

Section: Methodsmentioning

confidence: 99%

“…On cooling of the reaction mixture, pure crystals of 4 precipitated. Compound 16 was previously prepared in this laboratory [11,12]. The carbamates 16 and 19 were obtained by reaction of the corresponding hydroxamic acids with trimethylsilylisocyanate (Acros) and 6 purified by recrystallization from aqueous ethanol.…”

Section: Methodsmentioning

confidence: 99%

“…They act by crosslinking the active site between the nucleophilic serine and an adjacent conserved lysine [11]. The β-lactamases have active site similarity to another family of serine/lysine amidohydrolases, the N-terminal nucleophile peptidases, which are also inhibited by 15 in a manner that crosslinks the active site between hydroxyl and amine groups of the N-terminal threonine/serine [8].…”

Section: Inhibition By O-acyl Hydroxamic Acidsmentioning

confidence: 99%

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Specificity and mechanism of mandelamide hydrolase catalysis

Adediran

Wang

Shilabin

et al. 2017

Archives of Biochemistry and Biophysics

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The best-studied amidase signature (AS) enzyme is probably fatty acid amide hydrolase (FAAH). Closely related to FAAH is mandelamide hydrolase (MAH), whose substrate specificity and mechanism of catalysis are described in this paper. First, we developed a convenient chromogenic substrate, 4-nitrophenylacetamide, for MAH. The lack of reactivity of MAH with the corresponding ethyl ester confirmed the very limited size of the MAH leaving group site. The reactivity of MAH with 4-nitrophenyl acetate and methyl 4-nitrophenyl carbonate, therefore, suggested formation of an "inverse" acyl-enzyme where the small acylgroup occupies the normal leaving group site. We have interpreted the specificity of MAH for phenylacetamide substrates and small leaving groups in terms of its active site structure, using a homology model based on a FAAH crystal structure. The relevant structural elements were compared with those of FAAH. Phenylmethylboronic acid is a potent inhibitor of MAH (K i = 27 nM), presumably because it forms a transition state analogue structure with the enzyme. O-Acyl hydroxamates were not irreversible inactivators of MAH but some were found to be transient inhibitors.3

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O-Aryloxycarbonyl Hydroxamates: New β-Lactamase Inhibitors That Cross-Link the Active Site

Cited by 36 publications

References 14 publications

Three Decades of β-Lactamase Inhibitors

Three Decades of β-Lactamase Inhibitors

Fragment-Based Inhibitor Discovery Against β-Lactamase

Specificity and mechanism of mandelamide hydrolase catalysis

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