.GAMMA.-Lactam analogues of .BETA.-lactam antibiotics.

Baldwin, Jack E.; Lynch, Gregory P.; Pitlik, J.

doi:10.7164/antibiotics.44.1

Cited by 72 publications

(47 citation statements)

References 64 publications

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“…31,32 Second, the tetrahedral bridgehead nitrogen of bicyclic β -lactam antibiotics is important for affinity, because γ -lactam analogues of the penicillins, which have a planar bridgehead nitrogen, are not substrates of the Bacillus cereus BcII MBL. 33 …”

Section: Resultsmentioning

confidence: 99%

Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase

et al. 2015

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Pathogenic Gram-negative bacteria resistant to almost all β-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-β-lactamases (MBLs) produced by these bacteria inactivate most β-lactam antibiotics, including the carbapenems, which are “last line therapies” for life-threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of β-lactam substrates, which can be modified with metal-binding groups to target the MBL active site. Inspired by known interactions of MBLs with β-lactams, we designed four BTZs that behave as in vitro NDM-1 inhibitors with Ki values in the low micromolar range (from 7 ± 1 to 19 ± 3 μM). NMR spectroscopy demonstrated that they inhibit hydrolysis of imipenem in NDM-1-producing Escherichia coli. In vitro time kill cell-based assays against a variety of bacterial strains harboring blaNDM-1 including Acinetobacter baumannii show that the compounds restore the antibacterial activity of imipenem. A crystal structure of the most potent heterocycle (L-CS319) in complex with NDM-1 at 1.9 Å resolution identified both structural determinants for inhibitor binding and opportunities for further improvements in potency.

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Section: Resultsmentioning

confidence: 99%

Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase

et al. 2015

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“…In fact, work on non-β-lactam analogues of the β-lactams had begun in the early days of structure activity studies on the β-lactam antibacterials, with analogues of the penams [80,81]. In the mid-1980s, this work led to the identification of 5,4-and 5,5-lactam ring systems, of which some of the penem analogues displayed antibacterial activity (Figure 5), though the molecular mechanisms underlying the structure activity studies were not apparent at the time.…”

Section: Future Science Groupmentioning

confidence: 99%

“…In the mid-1980s, this work led to the identification of 5,4-and 5,5-lactam ring systems, of which some of the penem analogues displayed antibacterial activity (Figure 5), though the molecular mechanisms underlying the structure activity studies were not apparent at the time. At least in some cases, the antibacterial activity was associated with the increased reactivity of the unsaturated, compared with the saturated, γ-lactams (which as indicated above may be only one factor) [42,77,[80][81][82][83][84].…”

Section: Future Science Groupmentioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

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Avibactam, which is the first non-β-lactam β-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine β-lactamase inhibitor with activity against class A, class C, and, some, class D β-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-β-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and β-lactamase inhibitors. Like the β-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, avibactam reacts reversibly with its β-lactamase targets. We discuss chemical factors that may account for the apparently special nature of β-lactams and related compounds as antibacterials and β-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-β-lactam antibacterials acting similarly to β-lactams are discussed.

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“…In the field of antibiotics, [2] a lot of works has been devoted to the search of more strained, fused bicyclic b- [10,11] and g- [12,13] lactam systems.…”

Section: Introductionmentioning

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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.GAMMA.-Lactam analogues of .BETA.-lactam antibiotics.

Cited by 72 publications

References 64 publications

Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase

Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

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

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