Cargando…

2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases

Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safe...

Descripción completa

Detalles Bibliográficos
Autores principales: Rossi, Maria-Agustina, Martinez, Veronica, Hinchliffe, Philip, Mojica, Maria F., Castillo, Valerie, Moreno, Diego M., Smith, Ryan, Spellberg, Brad, Drusano, George L., Banchio, Claudia, Bonomo, Robert A., Spencer, James, Vila, Alejandro J., Mahler, Graciela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179362/
https://www.ncbi.nlm.nih.gov/pubmed/34164056
http://dx.doi.org/10.1039/d0sc05172a
_version_ 1783703763441156096
author Rossi, Maria-Agustina
Martinez, Veronica
Hinchliffe, Philip
Mojica, Maria F.
Castillo, Valerie
Moreno, Diego M.
Smith, Ryan
Spellberg, Brad
Drusano, George L.
Banchio, Claudia
Bonomo, Robert A.
Spencer, James
Vila, Alejandro J.
Mahler, Graciela
author_facet Rossi, Maria-Agustina
Martinez, Veronica
Hinchliffe, Philip
Mojica, Maria F.
Castillo, Valerie
Moreno, Diego M.
Smith, Ryan
Spellberg, Brad
Drusano, George L.
Banchio, Claudia
Bonomo, Robert A.
Spencer, James
Vila, Alejandro J.
Mahler, Graciela
author_sort Rossi, Maria-Agustina
collection PubMed
description Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., K(i) = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry.
format Online
Article
Text
id pubmed-8179362
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher The Royal Society of Chemistry
record_format MEDLINE/PubMed
spelling pubmed-81793622021-06-22 2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases Rossi, Maria-Agustina Martinez, Veronica Hinchliffe, Philip Mojica, Maria F. Castillo, Valerie Moreno, Diego M. Smith, Ryan Spellberg, Brad Drusano, George L. Banchio, Claudia Bonomo, Robert A. Spencer, James Vila, Alejandro J. Mahler, Graciela Chem Sci Chemistry Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., K(i) = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry. The Royal Society of Chemistry 2021-01-05 /pmc/articles/PMC8179362/ /pubmed/34164056 http://dx.doi.org/10.1039/d0sc05172a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Rossi, Maria-Agustina
Martinez, Veronica
Hinchliffe, Philip
Mojica, Maria F.
Castillo, Valerie
Moreno, Diego M.
Smith, Ryan
Spellberg, Brad
Drusano, George L.
Banchio, Claudia
Bonomo, Robert A.
Spencer, James
Vila, Alejandro J.
Mahler, Graciela
2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases
title 2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases
title_full 2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases
title_fullStr 2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases
title_full_unstemmed 2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases
title_short 2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases
title_sort 2-mercaptomethyl-thiazolidines use conserved aromatic–s interactions to achieve broad-range inhibition of metallo-β-lactamases
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179362/
https://www.ncbi.nlm.nih.gov/pubmed/34164056
http://dx.doi.org/10.1039/d0sc05172a
work_keys_str_mv AT rossimariaagustina 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT martinezveronica 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT hinchliffephilip 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT mojicamariaf 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT castillovalerie 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT morenodiegom 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT smithryan 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT spellbergbrad 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT drusanogeorgel 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT banchioclaudia 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT bonomoroberta 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT spencerjames 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT vilaalejandroj 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases
AT mahlergraciela 2mercaptomethylthiazolidinesuseconservedaromaticsinteractionstoachievebroadrangeinhibitionofmetalloblactamases