Synthesis and biological evaluation of Aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance

Zhang, Jian; Wang, Sanshan; Wei, Qi; Guo, Qianqian; Bai, Yanjie; Yang, Shengnan; Song, Fuhang; Zhang, Lixin; Lei, Xiaoguang

doi:10.1016/j.bmc.2017.07.025

Cited by 42 publications

(33 citation statements)

References 25 publications

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“…Of these, the fungal natural product aspergillomarasmine A (AMA, IC 50 =4–7 μM, Figure ), an aminopolycarboxylic acid, has gained attention due to its ability to restore meropenem activity in mice infected with NDM‐1 expressing Klebsiella pneumoniae . AMA inhibitor development has focused on modification of the carboxylic acid functional groups through removal or conversion to an ester motif, or exploration of related aminocarboxylic acid analogues . AMA‐1 and AMA‐2 (Figure ), where one of the carboxylate groups is replaced with a methyl substituent yielded weaker inhibition (IC 50 =22 and 94 μM, respectively) compared to that of AMA, validating the requirement of free carboxylic acids for enzyme inactivation and supporting the mechanism of action of AMA is via non‐selective Zn II sequestration (similar to that of EDTA).…”

Section: Introductionmentioning

confidence: 99%

Iminodiacetic Acid as a Novel Metal‐Binding Pharmacophore for New Delhi Metallo‐β‐lactamase Inhibitor Development

Chen

Thomas

et al. 2020

ChemMedChem

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The fungal natural product aspergillomarasmine A (AMA) has been identified as a noncompetitive inhibitor of New Delhi metallo‐β‐lactamase‐1 (NDM‐1) that inhibits by removing ZnII from the active‐site. The nonselective metal‐chelating properties and difficult synthesis and derivatization of AMA have hindered the development of this scaffold into a potent and selective inhibitor of NDM‐1. Iminodiacetic acid (IDA) has been identified as the metal‐binding pharmacophore (MBP) core of AMA that can be leveraged for inhibitor development. Herein, we report the use of IDA for fragment‐based drug discovery (FBDD) of NDM‐1 inhibitors. IDA (IC50=120 μM) was developed into inhibitor 23 f (IC50=8.6 μM, Ki=2.6 μM), which formed a ternary complex with NDM‐1, as evidenced by protein thermal‐shift and native‐state electrospray ionization mass spectrometry (ESI‐MS) experiments. Combining mechanistic analysis with inhibitor derivatization, the use of IDA as an alternative AMA scaffold for NDM‐1 inhibitor development is detailed.

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Section: Introductionmentioning

confidence: 99%

Iminodiacetic Acid as a Novel Metal‐Binding Pharmacophore for New Delhi Metallo‐β‐lactamase Inhibitor Development

Chen

Thomas

et al. 2020

ChemMedChem

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“…6 This finding was followed by reports describing the chemical synthesis of AMA and its structural analogues. [7][8][9][10][11] Among them, synthetic routes using either a key N-nosyl protected aziridine intermediate 10 or a cyclic sufamidate 9 furnished AMA in relatively few steps and the highest reported yields (overall yields of 28% and 19% respectively).…”

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confidence: 99%

Aminocarboxylic acids related to aspergillomarasmine A (AMA) and ethylenediamine-N,N′-disuccinic acid (EDDS) are strong zinc-binders and inhibitors of the metallo-beta-lactamase NDM-1

Tehrani

Brüchle

et al. 2020

Chem. Commun.

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“…The results not only confirmed the mechanism which AMA inhibited MBLs by removing Zn 2+ , but also revealed that 2 equivalents of AMA can effectively remove 1 equivalent of Zn 2+ from micromolar concentrations of NDM‐1, VIM‐2, and IMP‐7. Four synthetic routes for the production of AMA have been reported, and the stereochemical partitioning and structure–activity relationship of compounds have been explored (Albu et al., ; Koteva, King, Capretta, & Wright, ; Liao et al., ; ). These studies show that the 2″S, 2′S, 2S isomer of AMA (originally proposed as 2″R, 2′R, 2S) is the actual MBL inactivating agent.…”

Section: Progress In Designing Metallo‐β‐lactamase Inhibitorsmentioning

confidence: 99%

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

et al. 2019

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After more than 80 years of development, β‐lactam drugs have become the most widely used high‐efficiency, low‐toxic broad‐spectrum antibacterial drugs. However, with the widespread use and even abuse of those drugs, the resistance of major pathogens to β‐lactam drugs has increased over years, which has become a thorny problem to the public health. A common mechanism of the resistance to β‐lactams is the producing of β‐lactamases, which can hydrolyze the β‐lactam ring and inactivate these drugs. Metallo‐β‐lactamases (MBLs) are one kind of β‐lactamases that require metal ions for their catalytic activities. Although it is a well‐known strategy to recover the efficacy of β‐lactams by the combination of β‐lactamase inhibitors, there are still no MBL inhibitors that can be used in clinical practice. Therefore, it is urgent to develop MBL inhibitors. This review outlines the currently discovered MBL inhibitors with an emphasis on various strategies and approaches taken to discover MBL inhibitors, which may lead to diverse classes of inhibitors. Recent progress, particularly new screening methods, and the rational design of potent MBL inhibitors are discussed.

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Synthesis and biological evaluation of Aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance

Cited by 42 publications

References 25 publications

Iminodiacetic Acid as a Novel Metal‐Binding Pharmacophore for New Delhi Metallo‐β‐lactamase Inhibitor Development

Iminodiacetic Acid as a Novel Metal‐Binding Pharmacophore for New Delhi Metallo‐β‐lactamase Inhibitor Development

Aminocarboxylic acids related to aspergillomarasmine A (AMA) and ethylenediamine-N,N′-disuccinic acid (EDDS) are strong zinc-binders and inhibitors of the metallo-beta-lactamase NDM-1

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

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