Targeting clinically-relevant metallo-<b>β</b>-lactamases: from high-throughput docking to broad-spectrum inhibitors

Brindisi, Margherita; Brogi, Simone; Giovani, Simone; Gemma, Sandra; Lamponi, Stefania; Luca, Filomena De; Novellino, Ettore; Campiani, Giuseppe; Docquier, J.D.; Butini, Stefania

doi:10.3109/14756366.2016.1172575

Cited by 22 publications

(21 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…None of them contained sub‐structural features that would label them as “frequent hitters” in high‐throughput screens . The three‐dimensional structure of Zmp1 (PDB ID: http://www.rcsb.org/pdb/explore/explore.do?structureId=3ZUK) was taken from the RCSB Protein Data Bank, imported into Maestro, and prepared as described previously …”

Section: Methodsmentioning

confidence: 99%

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

et al. 2018

Self Cite

View full text Add to dashboard Cite

The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.

show abstract

Section: Methodsmentioning

confidence: 99%

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Compound 65 interacted with the metal ion of NDM-1. Moreover, it potentiated the activity of cefoxitin on a VIM-2-producing E. colistrain in vitro [79].…”

Section: Quinoline Inhibitorsmentioning

confidence: 88%

The Development of New Small-Molecule Inhibitors Targeting Bacterial Metallo-β-lactamases

Wang

Cheng

Liu

et al. 2018

CTMC

View full text Add to dashboard Cite

Metallo-β-lactamases (MBLs) are a family of Zn(II)-dependent enzymes that can hydrolyze almost all β-lactam antibiotics. Horizontal transfer of the genes encoding MBLs among Gram-negative bacteria pathogens has led to the emergence of extensively drug-resistant pathogens, which now represent a major threat to human health. As there is not to date yet a clinically available MBL inhibitor, the discovery of new MBL inhibitors has great urgency. This review highlights the recent developments in the discovery of small-molecule MBL inhibitors.

show abstract

Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors

Cited by 22 publications

References 48 publications

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

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

The Development of New Small-Molecule Inhibitors Targeting Bacterial Metallo-β-lactamases

Contact Info

Product

Resources

About