Polypyridine ligands as potential metallo-β-lactamase inhibitors

Piana, Luana La; Viaggi, Valentina; Principe, Luigi; Bella, Stefano Di; Luzzaro, Francesco; Viale, Maurizio; Bertola, Nadia; Vecchio, Graziella

doi:10.1016/j.jinorgbio.2020.111315

Cited by 9 publications

(4 citation statements)

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“…Ester compounds exhibit antimicrobial and antifungal inhibition activities against some Gram-positive and Gram-negative bacteria, having antifungal and antioxidant activity [ 14 , 15 , 16 , 17 ]. Evidence suggests hydrazide to have noteworthy antibacterial potential [ 18 ]. Some hydrazide–hydrazone analogues were demonstrated to have excellent inhibition properties against pathogenic organisms, with some having better antimicrobial activity when compared with known antibiotics [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and Biological Evaluation of Novel Benzamidine Derivatives: Newer Antibiotics for Periodontitis Treatment

et al. 2022

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Periodontal disease (PD) is complex polymicrobial disease which destroys tooth-supporting tissue. Although various synthetic inhibitors of periodontitis-triggering pathogens have been recognized, their undesirable side effects limit their application. Hence, the present study intended to perform the synthesis, characterization, antimicrobial evaluation, and cytotoxicity analysis of novel benzamidine analogues (NBA). This study involved the synthesis of novel imino bases of benzamidine (4a–c), by reacting different aromatic aldehydes with 2-(4-carbamimidoylphenoxy) acetohydrazide (3), which was synthesized by the hydrazination of ethyl 2-(4-carbamimidoylphenoxy) acetate (2), the derivative of 4-hydroxybenzene carboximidamide (1). This was followed by characterization using FTIR, 1H, 13C NMR and mass spectrometry. All synthesized compounds were further tested for antimicrobial potential against PD-triggering pathogens by the micro broth dilution method. The cytotoxicity analysis of the NBA against HEK 293 cells was conducted using an MTT assay. The present study resulted in a successful synthesis of NBA and elucidated their structures. The synthesized NBA exhibited significant antimicrobial activity values between 31.25 and 125 µg/mL against tested pathogens. All NBA exhibited weak cytotoxicity against HEK 293 cells at 7.81 µg, equally to chlorhexidine at 0.2%. The significant antimicrobial activity of NBA against PD-triggering pathogens supports their potential application in periodontitis treatment.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization and Biological Evaluation of Novel Benzamidine Derivatives: Newer Antibiotics for Periodontitis Treatment

et al. 2022

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“…Combined, these data demonstrate, for the first time, a potential mechanism(s) of action, involving disruption of intracellular zinc homeostasis, for GT/DTG-mediated bacterial growth inhibition. Moreover, it complements the work of others who have deployed a range of zinc chelators (e.g., TPEN, reduced holomycin, D-alanyl-D-alanyl-D-alanine methyl ester functionalized N,N,N'-tris(2-pyridylmethyl)-ethylenediamine and tris-picolylamine (TPA) to overcome MBL degradation of target antibiotics 32 , 42 , 44 , 45 . Conversely, in pioneering work, microarray analysis of E. faecalis exposure to Zn and Cu revealed that two modules were implicated in the microbial response to metal exposure 46 .…”

Section: Resultsmentioning

confidence: 60%

Gliotoxin-mediated bacterial growth inhibition is caused by specific metal ion depletion

Downes,

Owens,

Walshe

et al. 2023

Sci Rep

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Overcoming antimicrobial resistance represents a formidable challenge and investigating bacterial growth inhibition by fungal metabolites may yield new strategies. Although the fungal non-ribosomal peptide gliotoxin (GT) is known to exhibit antibacterial activity, the mechanism(s) of action are unknown, although reduced gliotoxin (dithiol gliotoxin; DTG) is a zinc chelator. Furthermore, it has been demonstrated that GT synergises with vancomycin to inhibit growth of Staphylococcus aureus. Here we demonstrate, without precedent, that GT-mediated growth inhibition of both Gram positive and negative bacterial species is reversed by Zn2+ or Cu2+ addition. Both GT, and the known zinc chelator TPEN, mediate growth inhibition of Enterococcus faecalis which is reversed by zinc addition. Moreover, zinc also reverses the synergistic growth inhibition of E. faecalis observed in the presence of both GT and vancomycin (4 µg/ml). As well as zinc chelation, DTG also appears to chelate Cu2+, but not Mn2+ using a 4-(2-pyridylazo)resorcinol assay system and Zn2+ as a positive control. DTG also specifically reacts in Fe3+-containing Siderotec™ assays, most likely by Fe3+ chelation from test reagents. GSH or DTT show no activity in these assays. Confirmatory high resolution mass spectrometry, in negative ion mode, confirmed, for the first time, the presence of both Cu[DTG] and Fe[DTG]2 chelates. Label free quantitative proteomic analysis further revealed major intracellular proteomic remodelling within E. faecalis in response to GT exposure for 30–180 min. Globally, 4.2–7.2% of detectable proteins exhibited evidence of either unique presence/increased abundance or unique absence/decreased abundance (n = 994–1160 total proteins detected), which is the first demonstration that GT affects the bacterial proteome in general, and E. faecalis, specifically. Unique detection of components of the AdcABC and AdcA-II zinc uptake systems was observed, along with apparent ribosomal reprofiling to zinc-free paralogs in the presence of GT. Overall, we hypothesise that GT-mediated bacterial growth inhibition appears to involve intracellular zinc depletion or reduced bioavailability, and based on in vitro chelate formation, may also involve dysregulation of Cu2+ homeostasis.

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“…Finally, the hydrolysis reaction of esters described as above was performed to synthesize the title compound 23 in 71% yield as a yellowish liquid, 99.3% HPLC purity. 2-Amino-5-(4-(but-3-en-1-yloxy)benzyl)thiazole-4-carboxylic Acid (24). The title compound was prepared in a manner similar to that for compound 23, 18% yield for five steps, 96.7% 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%

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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Polypyridine ligands as potential metallo-β-lactamase inhibitors

Cited by 9 publications

References 64 publications

Synthesis, Characterization and Biological Evaluation of Novel Benzamidine Derivatives: Newer Antibiotics for Periodontitis Treatment

Synthesis, Characterization and Biological Evaluation of Novel Benzamidine Derivatives: Newer Antibiotics for Periodontitis Treatment

Gliotoxin-mediated bacterial growth inhibition is caused by specific metal ion depletion

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

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