Novel mechanism of inhibiting β-Lactamases by sulfonylation using β-Sultams

Page, Michael I.; Hinchliffe, Paul S.; Wood, J. Matthew; Harding, Lindsay P.; Laws, Andrew P.

doi:10.1016/j.bmcl.2003.08.082

Cited by 28 publications

(13 citation statements)

References 33 publications

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“…1, compound 29) inactivate the P99 enzyme (318,419). ESI-MS studies suggest that the ␤-sultams sulfonylate the serine residue to form a sulfonate ester.…”

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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“…1, compound 29) inactivate the P99 enzyme (318,419). ESI-MS studies suggest that the ␤-sultams sulfonylate the serine residue to form a sulfonate ester.…”

Section: Non-␤-lactam Inhibitorsmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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“…Thus, targeting these enzymes, particularly the broad-spectrum class C serine and class B metalloenzymes, will remain an active area of investigation [342,347]. Indeed, recent reports highlight a number of novel inhibitors, some of which are themselves b-lactams [348][349][350][351], of class C [348][349][350][351][352][353][354][355][356] and class B [357][358][359][360][361][362][363] enzymes (see also several references in [342]). Several of the class C inhibitors have demonstrated activity against class A enzymes, including ESBLs, [342, 349-351, 355, 356] and class D enzymes [350,356], and potentiate the activity of b-lactams against b-lactamase-producing organisms [342,349,350,353,354,364].…”

Section: B B-lactamasesmentioning

confidence: 99%

Resistance to ?-lactam antibiotics

Poole

2004

CMLS, Cell. Mol. Life Sci.

288

218

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beta-lactams have a long history in the treatment of infectious diseases, though their use has been and continues to be confounded by the development of resistance in target organisms. beta-lactamases, particularly in Gram-negative pathogens, are a major determinant of this resistance, although alterations in the beta-lactam targets, the penicillin-binding proteins (PBPs), are also important, especially in Gram-positive pathogens. Mechanisms for the efflux and/or exclusion of these agents also contribute, though often in conjunction these other two. Approaches for overcoming these resistance mechanisms include the development of novel beta-lactamase-stable beta-lactams, beta-lactamase inhibitors to be employed with existing beta-lactams, beta-lactam compounds that bind strongly to low-affinity PBPs and agents that potentiate the activity of existing beta-lactams against low-affinity PBP-producing organisms.

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“…The field is dominated by the β-lactams (1) [ Figure 1] due to the importance that they have acquired as anti-infective agents. [1][2][3] The corresponding β-sultams (2) are also known and have attracted attention as taurine precursors, 4,5 β-lactamase inhibitors, 6 D,D-peptidase inhibitors, 7 human neutrophil elastase inhibitors, [8][9][10] azoreductase inhibitors, 11 anti-inflammatory agents, 12 potential treatments for alcohol dependency, 13 SPase I inhibitors 14 and ClpP protease inhibitors, 15 and have attracted other mechanistic 16,17 and synthetic efforts. [18][19][20] β-Sultam chemistry been a focus of our research for some time.…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20] β-Sultam chemistry been a focus of our research for some time. [6][7][8][9][10]12,13,17 …”

Section: Introductionmentioning

confidence: 99%

Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides

et al. 2016

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Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low μM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

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Novel mechanism of inhibiting β-Lactamases by sulfonylation using β-Sultams

Cited by 28 publications

References 33 publications

Three Decades of β-Lactamase Inhibitors

Three Decades of β-Lactamase Inhibitors

Resistance to ?-lactam antibiotics

Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides

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