A new selective inhibitor for IMP-1 metallo-β-lactamase, 3Z,5E-octa-3,5-diene-1,3,4-tricarboxylic acid-3,4-anhydride

Ikeda, Akari; Ikegaya, Yoshiki; Honsho, Masako; Matsui, Hidehito; Nonaka, Kenichi; Ishii, Takahiro; Asami, Yukihiro; Hanaki, Hideaki; Hirose, Tomoyasu; Sunazuka, Toshiaki

doi:10.1016/j.bmc.2022.117109

Cited by 4 publications

(7 citation statements)

References 25 publications

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“…Therefore, the discovery of novel compounds capable of inhibiting MBL enzymes is of paramount importance to restore antibiotic effectiveness against life-threatening and challenging-to-treat bacterial infections. To assess the potential of elasnins as β-lactamase inhibitors, we employed the nitrocefin method, a widely recognized approach in which the synthetic β-lactam nitrocefin undergoes a characteristic color change upon lactam ring opening by β-lactamases. Nitrocefin initially exhibits UV absorption at λ max 391 nm (colorless), but enzymatic hydrolysis causes a red shift to λ max 491 nm (red).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, none of the proelasnins exhibited any MBL inhibitory activity, suggesting that the acyl chain attached to C-6 (alkyl chain 1) is crucial for MBL inhibition. Subsequently, the effectiveness of meropenem (MEPM) against drug-resistant Escherichia coli KB366 expressing MBL was evaluated in the presence of 5 , 8 , and 10 using the agar disk diffusion method; however, no enhancement in MEPM activity was recorded.…”

Section: Resultsmentioning

confidence: 99%

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Expression of Syo_1.56 SARP Regulator Unveils Potent Elasnin Derivatives with Antibacterial Activity

A. Abdelhakim,

Futamura,

Asami

et al. 2024

J. Nat. Prod.

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Actinomycetes are prolific producers of natural products, particularly antibiotics. However, a significant proportion of its biosynthetic gene clusters (BGCs) remain silent under typical laboratory conditions. This limits the effectiveness of conventional isolation methods for the discovery of novel natural products. Genetic interventions targeting the activation of silent gene clusters are necessary to address this challenge. Streptomyces antibiotic regulatory proteins (SARPs) act as cluster-specific activators and can be used to target silent BGCs for the discovery of new antibiotics. In this study, the expression of a previously uncharacterized SARP protein, Syo_1.56, in Streptomyces sp. RK18-A0406 significantly enhanced the production of known antimycins and led to the discovery of 12 elasnins (1−12), 10 of which were novel. The absolute stereochemistry of elasnin A 1 was assigned for the first time to be 6S. Unexpectedly, Syo_1.56 seems to function as a pleiotropic rather than cluster-specific SARP regulator, with the capability of co-regulating two distinct biosynthetic pathways, simultaneously. All isolated elasnins were active against wild-type and methicillin-resistant Staphylococcus aureus with IC 50 values of 0.5−20 μg/mL, some of which (elasnins A 1 , B 2 , and C 1 and proelasnins A 1 , and C 1 ) demonstrated moderate to strong antimalarial activities against Plasmodium falciparum 3D7. Elasnins A 1 , B 3 , and C 1 also showed in vitro inhibition of the metallo-β-lactamase responsible for the development of highly antibiotic-resistant bacterial strains.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Expression of Syo_1.56 SARP Regulator Unveils Potent Elasnin Derivatives with Antibacterial Activity

A. Abdelhakim,

Futamura,

Asami

et al. 2024

J. Nat. Prod.

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“…1 H NMR (400 MHz, DMSOd 6 ) δ: 8.68 (s, 2H), 2.97 (t, J = 7.2 Hz, 2H), 1.61−1.54 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H) ppm. 13 2-Amino-5-(sec-butyl)thiazole-4-carboxylic Acid (31). The target compound was obtained using a method similar to that for 1, 65% yield for two steps, 95.6% HPLC purity.…”

Section: -Amino-5-(4-(trifluoromethyl)benzyl)thiazole-4-carboxylic Ac...mentioning

confidence: 99%

“…The target compound was obtained using a method similar to that for 1, 53% yield for two steps, 99.6% HPLC purity. 1 2-Amino-5-(sec-butyl)thiazole-4-carboxylic Acid (31). The target compound was obtained using a method similar to that for 1, 65% yield for two steps, 95.6% HPLC purity.…”

Section: -Amino-5-(4-(trifluoromethyl)benzyl)thiazole-4-carboxylic Ac...mentioning

confidence: 99%

“…MBLs are zinc-dependent metalloenzymes, which utilize Zn(II)-bound hydroxyl for β-lactam hydrolysis . Various inhibitor chemotypes have been reported to target MBLs, − which can be broadly classified as type I–V inhibitors based on the proposed mechanisms of MBL-mediated β-lactam hydrolysis (Figure ). The potent and broad-spectrum MBL inhibitors typically achieve their efficacy by mimicking key features of complexes involved in β-lactam binding and reactions, albeit at different phases of catalysis. , Currently, three drug candidates, namely VNRX-5133 (taniborbactam), QPX7728 (xeruborbactam), and QPX7831, which are dual MBL/SBL inhibitors, are undergoing evaluation in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding

Yan,

Zhang,

et al. 2023

J. Med. Chem.

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Metallo-β-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic β-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance.

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A novel aromatic compound from the fungus Synnemellisia sp. FKR-0921

Tahara,

Tani,

Wakatsuki

et al. 2023

J Antibiot

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A new selective inhibitor for IMP-1 metallo-β-lactamase, 3Z,5E-octa-3,5-diene-1,3,4-tricarboxylic acid-3,4-anhydride

Cited by 4 publications

References 25 publications

Expression of Syo_1.56 SARP Regulator Unveils Potent Elasnin Derivatives with Antibacterial Activity

Expression of Syo_1.56 SARP Regulator Unveils Potent Elasnin Derivatives with Antibacterial Activity

Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding

A novel aromatic compound from the fungus Synnemellisia sp. FKR-0921

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