4-Substituted Trinems as Broad Spectrum β-Lactamase Inhibitors:  Structure-Based Design, Synthesis, and Biological Activity

Plantan, Ivan; Selič, Lovro; Mesar, Tomaž; Anderluh, Marko; Oblak, Marko; Prezelj, Andrej; Hesse, Lars; Andrejašič, Miha; Vilar, Mateja; Turk, Dušan; Kocijan, Andrej; Prevec, Tadeja; Vilfan, Gregor; Kocjan, Darko; Copar, Anton; Urleb, U.; Šolmajer, Tom

doi:10.1021/jm0703237

Cited by 36 publications

(45 citation statements)

References 56 publications

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“…1, compound 20) was derived by introduction of a methoxy substituent at position C-4 and shows nM affinity for both the class A TEM-1 and class C E. cloacae 908R ␤-lactamases (431). The IC 50 s of clavulanate and LK-157 for TEM-1 were similar (0.030 M and 0.055 M, respectively), but that of LK-157 was over 2000-fold better for E. cloacae AmpC (136.2 M and 0.062 M, respectively) (344). In combination with ampicillin, LK-157 (at 30 g/ml) restored susceptibility for the AmpC-overexpressing E. cloacae P99 strain in MIC testing (431).…”

Section: Brl 42715 Derivativesmentioning

confidence: 92%

“…The crystal structure of LK-157 in complex with the E. cloacae P99 (PDB 2Q9N), together with spectroscopic data for reaction intermediates, suggests that after deacylation at the active-site Ser64, the C-4 methoxy group is eliminated (344,431). Further, the catalytic water molecule presumed to be responsible for deacylation in class C enzymes is not observed in the AmpC/LK-157 crystal structure.…”

Section: Brl 42715 Derivativesmentioning

confidence: 99%

“…Further, the catalytic water molecule presumed to be responsible for deacylation in class C enzymes is not observed in the AmpC/LK-157 crystal structure. Rotation about the opened ␤-lactam ring after acylation likely leads to displacement of this water molecule and subsequent enzyme inhibition (344). The C-10 ethyldiene group is probably not bulky enough to induce the conformational change seen with inhibition of class A enzymes by carbapenems, but resonance stabilization of the acyl-enzyme through the acyl carbonyl and ethyldiene group may contribute to stability of the intermediate (255,344).…”

Section: Brl 42715 Derivativesmentioning

confidence: 99%

“…Rotation about the opened ␤-lactam ring after acylation likely leads to displacement of this water molecule and subsequent enzyme inhibition (344). The C-10 ethyldiene group is probably not bulky enough to induce the conformational change seen with inhibition of class A enzymes by carbapenems, but resonance stabilization of the acyl-enzyme through the acyl carbonyl and ethyldiene group may contribute to stability of the intermediate (255,344). Trinems are worthy of attention for the potential to serve as leads for additional structure-based inhibitor design, and Lek Pharmaceuticals continues to investigate LK-157.…”

Section: Brl 42715 Derivativesmentioning

confidence: 99%

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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: Brl 42715 Derivativesmentioning

confidence: 92%

Section: Brl 42715 Derivativesmentioning

confidence: 99%

Section: Brl 42715 Derivativesmentioning

confidence: 99%

Section: Brl 42715 Derivativesmentioning

confidence: 99%

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Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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“…Instead of increasing the angular strain and the N1 pyramidality (''twisted amide'') in the azetidinone ring of 1,4-fused bi- [64,65] or tricyclic systems [66], we considered flexible 1,3-bridged bicyclic systems featuring a ''planar amide'' and a large ring susceptible to generate a lot of conformers. Such azetidinones, endowed with a thienamycin-like side-chain at C3 and the related stereochemistry at C3-C5, are readily accessible via a convergent RCM strategy, as illustrated by the synthesis of the 13-membered bicycles E-11 and 12 from the commercial chiron 7, precursor of 10.…”

Section: Discussionmentioning

confidence: 99%

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies

Urbach

Dive

Tinant

et al. 2009

European Journal of Medicinal Chemistry

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a b s t r a c tThe relationship between angular strain and (re)activity of bicyclic 2-azetidinones is still an open question of major concern in the field of penicillin antibiotics. Our study deals with original 13-membered-ring 1,3-bridged 2-azetidinones related to the carbapenem family, and featuring a ''planar amide'' instead of the ''twisted amide'' typical of penam derivatives. The bicycles 11 and 12 were obtained from acetoxy-azetidinone 7, via the key-intermediate 10, by using the RCM (ring closing metathesis) strategy. Theoretical predictions and experimental results of hydrolysis showed that the large bicycle 12, endowed with high conformational flexibility, is more reactive than the bicycle 11, including a C]C bond of E configuration, and the monocyclic 2-azetidinone precursor 10. The processing of 2-azetidinones 10-12 in the active site of serine enzymes has been computed by ab initio methods, considering three models. Due to geometrical parameters of the enzymic cavity (nucleophilic attack from the a-face), precursor 10 was predicted more active than 11 and 12 in the acylation step by Ser-OH.Indeed, bicycles 11 and 12 are modest inhibitors of PBP 2a , while 10 is a good to excellent inhibitor of PBP 2a and R39 bacterial enzymes.

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β‐Lactam Antibiotics

Testero

Fisher

Mobashery

2010

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β‐lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β‐lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β‐lactam resistance, alterations to the molecular targets of the β‐lactams (the penicillin binding proteins) and the use of enzymes (the β‐lactamases) capable of the hydrolytic deactivation of the β‐lactams are paramount. This review traces the historical development of β‐lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β‐lactams leading to the discovery of new generation β‐lactam antibacterials effective against the Gram‐negative and ‐positive bacterial pathogens of current medical concern.

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4-Substituted Trinems as Broad Spectrum β-Lactamase Inhibitors: Structure-Based Design, Synthesis, and Biological Activity

Cited by 36 publications

References 56 publications

Three Decades of β-Lactamase Inhibitors

Three Decades of β-Lactamase Inhibitors

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies

β‐Lactam Antibiotics

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