NOTA: a potent metallo-β-lactamase inhibitor

Somboro, Anou M.; Tiwari, D. C.; Bester, Linda A.; Parboosing, Raveen; Chonco, Louis; Kruger, Hendrik G.; Arvidsson, Per I.; Govender, Thavendran; Naicker, Tricia; Essack, Sabiha Y.

doi:10.1093/jac/dku538

Cited by 55 publications

(50 citation statements)

References 11 publications

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“…The choice of isolates used in this study was based on our previous report where NOTA was described to inhibit MBL‐producing CREs but not CREs producing the serine‐based carbapenemases (Somboro et al . ). The ability of metal chelators to complex zinc in the active site of the MBL enzyme deactivates the hydrolysis of carbapenems.…”

Section: Discussionmentioning

confidence: 97%

“…While NOTA worked better in our previous studies, we must consider that its extremely polar and therefore does not share similar physico‐chemical properties of the drugs that it needs to combine with, that is, carbapenems (Somboro et al . ). These results would and always be limited to in vitro work; so to modify its pharmacological properties, NODAGA was derivatized with peptides containing N ‐methylated amino acids.…”

Section: Discussionmentioning

confidence: 97%

“…Our previous study has shown that NOTA is better at inactivating the MBL enzyme than DOTA, when tested against some CRE strains (Somboro et al . ). These unique properties may contribute to their future prospects in the treatment of infections caused by CREs producing MBLs with minimal cytotoxic effect.…”

Section: Discussionmentioning

confidence: 97%

“…Our previous study has shown that NOTA is better at inactivating the MBL enzyme than DOTA, when evaluated against some CRE strains (Somboro et al . ). Also, polypyridyls are acyclic chelators that have proven their ability to treat apoptosis‐resistant human cancer in vitro due to their strong zinc chelating properties (Zuo et al .…”

Section: Introductionmentioning

confidence: 97%

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In vitro evaluation of metal chelators as potential metallo- β -lactamase inhibitors

et al. 2016

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

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In vitro evaluation of metal chelators as potential metallo- β -lactamase inhibitors

et al. 2016

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“…To date, severalc hemical familiesh ave been reported to inhibit MBLs. They include biphenyltetrazoles, [14] various thiol-and thioester-containing compounds, [15][16][17][18][19][20][21][22][23][24][25][26][27] di- [28][29][30][31] and polycarboxylate compounds, [32][33][34] hydroxamates, [35] arylsulfonyl-containingc ompounds, [36][37][38][39][40] trifluoromethyl alcohols and ketones, [41] tricyclic natural compounds, [42] and cyclic boronates. [43] Approaches to covalent MBL inhibitors have also been considered.…”

Section: Introductionmentioning

confidence: 99%

1,2,4‐Triazole‐3‐thione Compounds as Inhibitors of Dizinc Metallo‐β‐lactamases

et al. 2017

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Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC values toward plasmodial glyoxalase II were in the 10 μm range.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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NOTA: a potent metallo-β-lactamase inhibitor

Cited by 55 publications

References 11 publications

In vitro evaluation of metal chelators as potential metallo- β -lactamase inhibitors

In vitro evaluation of metal chelators as potential metallo- β -lactamase inhibitors

1,2,4‐Triazole‐3‐thione Compounds as Inhibitors of Dizinc Metallo‐β‐lactamases

Medicinal Chemistry of β‐Lactam Antibiotics

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