Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance

ABSTRACT Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae. Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here tha...

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Autores principales:	Jun-ichi Wachino, Wanchun Jin, Kouji Kimura, Hiromasa Kurosaki, Ayato Sato, Yoshichika Arakawa
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	CRE sulfamoyl heteroarylcarboxylic acids carbapenems metallo-β-lactamase Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/06c7870989aa4b839f1bdca139f23749
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spelling	oai:doaj.org-article:06c7870989aa4b839f1bdca139f237492021-11-15T15:57:02ZSulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance10.1128/mBio.03144-192150-7511https://doaj.org/article/06c7870989aa4b839f1bdca139f237492020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03144-19https://doaj.org/toc/2150-7511ABSTRACT Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae. Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa. Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE. IMPORTANCE Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae. However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.Jun-ichi WachinoWanchun JinKouji KimuraHiromasa KurosakiAyato SatoYoshichika ArakawaAmerican Society for MicrobiologyarticleCREsulfamoyl heteroarylcarboxylic acidscarbapenemsmetallo-β-lactamaseMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	CRE sulfamoyl heteroarylcarboxylic acids carbapenems metallo-β-lactamase Microbiology QR1-502
spellingShingle	CRE sulfamoyl heteroarylcarboxylic acids carbapenems metallo-β-lactamase Microbiology QR1-502 Jun-ichi Wachino Wanchun Jin Kouji Kimura Hiromasa Kurosaki Ayato Sato Yoshichika Arakawa Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance
description	ABSTRACT Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae. Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa. Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE. IMPORTANCE Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae. However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.
format	article
author	Jun-ichi Wachino Wanchun Jin Kouji Kimura Hiromasa Kurosaki Ayato Sato Yoshichika Arakawa
author_facet	Jun-ichi Wachino Wanchun Jin Kouji Kimura Hiromasa Kurosaki Ayato Sato Yoshichika Arakawa
author_sort	Jun-ichi Wachino
title	Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance
title_short	Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance
title_full	Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance
title_fullStr	Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance
title_full_unstemmed	Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance
title_sort	sulfamoyl heteroarylcarboxylic acids as promising metallo-β-lactamase inhibitors for controlling bacterial carbapenem resistance
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/06c7870989aa4b839f1bdca139f23749
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_version_	1718427009177092096

Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance

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