Aspergillomarasmine A inhibits metallo-β-lactamases by selectively sequestering Zn2+

Sychantha, David; Rotondo, Caitlyn M.; Tehrani, Kamaleddin Haj Mohammad Ebrahim; Martin, Nathaniel I.; Wright, Gerard D.

doi:10.1016/j.jbc.2021.100918

Cited by 27 publications

(24 citation statements)

References 37 publications

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“…The sixth and final coordination site is occupied by a carboxylate oxygen (O7A) of an adjacently packed AMA-Ni 2+ complex, which we believe is a crystallization artifact. This hypothesis is based on our previous data, which showed that the binding of either Ni 2+ or Zn 2+ to AMA occurs with 1:1 stoichiometry in solution . Consequently, we suspect that the sixth coordination site of the AMA complex is likely occupied by solvent when dissolved under aqueous conditions.…”

Section: Resultsmentioning

confidence: 99%

“…In 2014, we identified a fungal Zn 2+ metallophore, aspergillomarasmine A (AMA) (Figure ), as an inhibitor of MBLs with excellent efficacy toward NDM and VIM-type enzymes. The mechanism of action of AMA involves selective Zn 2+ binding with picomolar affinity, which sequesters the metal in complex fluids . Consequently, AMA indirectly inhibits MBLs by outcompeting them for Zn 2+ even in the presence of common metals (Mg 2+ , Ca 2+ , and Fe 3+ ).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, AMA indirectly inhibits MBLs by outcompeting them for Zn 2+ even in the presence of common metals (Mg 2+ , Ca 2+ , and Fe 3+ ). AMA also promotes Zn 2+ dissociation from active sites of MBLs, which accelerates the degradation of certain types of MBLs (e.g., NDM-1) in bacteria . As a result, AMA restores the activity of β-lactams such as meropenem against MBL producing carbapenem-resistant bacteria in mouse models of infection while being well tolerated in the host (LD 50 > 150 mg/kg i.v.…”

Section: Introductionmentioning

confidence: 99%

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Three-Dimensional Structure and Optimization of the Metallo-β-Lactamase Inhibitor Aspergillomarasmine A

et al. 2022

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The aminopolycarboxylic acid aspergillomarasmine A (AMA) is a natural Zn 2+ metallophore and inhibitor of metalloβ-lactamases (MBLs) which reverses β-lactam resistance. The first crystal structure of an AMA coordination complex is reported and reveals a pentadentate ligand with distorted octahedral geometry. We report the solid-phase synthesis of 23 novel analogs of AMA involving structural diversification of each subunit (L-Asp, L-APA1, and L-APA2). Inhibitory activity was evaluated in vitro using five strains of Escherichia coli producing globally prevalent MBLs. Further in vitro assessment was performed with purified recombinant enzymes and intracellular accumulation studies. Highly constrained structure−activity relationships were demonstrated, but three analogs revealed favorable characteristics where either Zn 2+ affinity or the binding mode to MBLs were improved. This study identifies compounds that can further be developed to produce more potent and broader-spectrum MBL inhibitors with improved pharmacodynamic/pharmacokinetic properties.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Three-Dimensional Structure and Optimization of the Metallo-β-Lactamase Inhibitor Aspergillomarasmine A

et al. 2022

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“…Since NDM-1 has been found widely in a total of 11 bacterial host families, new variants of NDM containing between 1 and 5 amino acid alterations have been continually generated, which indicates that amino acid substitution dominates the extension of MBL activity ( Wu et al, 2019 ). A233V substitution enabled NDM-6 to evolve higher enzyme fitness in the periplasm under the Zn(II) starvation condition than NDM-1 ( Bahr et al, 2018 ; Sychantha et al, 2021 ). To date, there are four additional bla NDM–6 -harbouring plasmids with complete sequences deposited in NCBI, which belonged to incompatibility groups IncHI2, IncX3, IncFII, and IncR from Leclercia adecarboxylata , K. pneumoniae and E. coli.…”

Section: Discussionmentioning

confidence: 99%

Emergence of a Carbapenem-Resistant Klebsiella pneumoniae Isolate Co-harbouring Dual blaNDM– 6-Carrying Plasmids in China

et al. 2022

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The widespread emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) with limited therapeutic options has become a global concern. In this study, a K. pneumoniae strain called KP2e was recovered from a human case of fatal septic shock in a Chinese hospital. Polymerase chain reaction and sequencing, antimicrobial susceptibility testing, conjugation experiments, S1 nuclease-pulsed field gel electrophoresis/southern blot, whole genome sequencing and comparative genomics were performed to investigate the phenotypic and molecular characteristics of this isolate. KP2e possessed the NDM-6-encoding gene and exhibited resistance to almost all β-lactams except for monobactam. This strain belonged to sequence type 4024, the complete genome of which was composed of one chromosome and three plasmids. Furthermore, blaNDM–6 coexisted on two self-transmissible plasmids, which were assigned to types IncFIB and IncN. A structure of IS26-composite transposon capturing an identical Tn125 remnant (ΔISAba125-blaNDM–6-bleMBL-trpF-dsbC-cutA-groES-ΔgroEL) was identified in the two plasmids, and this conserved blaNDM-surrounding genetic context was similar to that of few IncN plasmids found in other regions of China. Our research appears to be the first description of a clinical strain that emerged co-harbouring dual blaNDM-carrying plasmids, and the first report of NDM-6-positive CRKP in China. These findings demonstrated that IncN is a key medium in the evolution and expanding dissemination of blaNDM genes among various species, which indicates that close monitoring and rapid detection of blaNDM-harbouring plasmids is necessary.

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“…Aspergillomarasmine A (AMA) is a fungal natural product considered a rapid and potent MBL inhibitor that electively sequesters Zn 2+ (King et al, 2014 ; Sychantha et al, 2021 ). AMA itself is not antimicrobial but works in combination with β-lactam antibiotics or carbapenems against MBL producers, with an emphasis on VIM or NDM.…”

Section: Natural Productsmentioning

confidence: 99%

Drug development concerning metallo-β-lactamases in gram-negative bacteria

et al. 2022

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β-Lactams have been a clinical focus since their emergence and indeed act as a powerful tool to combat severe bacterial infections, but their effectiveness is threatened by drug resistance in bacteria, primarily by the production of serine- and metallo-β-lactamases. Although once of less clinical relevance, metallo-β-lactamases are now increasingly threatening. The rapid dissemination of resistance mediated by metallo-β-lactamases poses an increasing challenge to public health worldwide and comprises most existing antibacterial chemotherapies. Regrettably, there have been no clinically available inhibitors of metallo-β-lactamases until now. To cope with this unique challenge, researchers are exploring multidimensional strategies to combat metallo-β-lactamases. Several studies have been conducted to develop new drug candidates or calibrate already available drugs against metallo-β-lactamases. To provide an overview of this field and inspire more researchers to explore it further, we outline some promising candidates targeting metallo-β-lactamase producers, with a focus on Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Promising candidates in this review are composed of new antibacterial drugs, non-antibacterial drugs, antimicrobial peptides, natural products, and zinc chelators, as well as their combinations with existing antibiotics. This review may provide ideas and insight for others to explore candidate metallo-β-lactamases as well as promote the improvement of existing data to obtain further convincing evidence.

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Aspergillomarasmine A inhibits metallo-β-lactamases by selectively sequestering Zn2+

Cited by 27 publications

References 37 publications

Three-Dimensional Structure and Optimization of the Metallo-β-Lactamase Inhibitor Aspergillomarasmine A

Three-Dimensional Structure and Optimization of the Metallo-β-Lactamase Inhibitor Aspergillomarasmine A

Emergence of a Carbapenem-Resistant Klebsiella pneumoniae Isolate Co-harbouring Dual blaNDM– 6-Carrying Plasmids in China

Drug development concerning metallo-β-lactamases in gram-negative bacteria

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