Dataset Information

Mercaptoacetate thioesters and their hydrolysate mercaptoacetic acids jointly inhibit metallo-?-lactamase L1.

ABSTRACT: The 'superbug' infection caused by metallo-?-lactamases (M?Ls) including L1 has grown into an emerging threat. To probe whether mercaptoacetate thioesters inhibiting L1 is a contribution of the thioester itself or its hydrolysate, ten mercaptoacetate thioesters 1-10 were synthesized, which specifically inhibited L1, exhibiting IC50 values ranging from 0.17 to 1.2 ?M, and 8 was found to be the best inhibitor (IC50 = 0.17 ?M). These thioesters restored the antimicrobial activity of cefazolin against E. coli expressing L1 by 2-4-fold. UV-vis monitoring showed that 1, 8 and 9 were unhydrolyzed in Tris buffer (pH 6.0-8.5), but hydrolyzed by L1; further HPLC monitoring indicated that 1/3 of the thioester 9 was converted to mercaptoacetic acid. STD-NMR monitoring suggested that both the thioester and its hydrolysate mercaptoacetic acid jointly inhibited L1.

SUBMITTER: Chen C

PROVIDER: S-EPMC6071727 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Mercaptoacetate thioesters and their hydrolysate mercaptoacetic acids jointly inhibit metallo-β-lactamase L1.

Chen Cheng C Xiang Yang Y Liu Ya Y Hu Xiangdong X Yang Ke-Wu KW

MedChemComm 20180517 7

The 'superbug' infection caused by metallo-β-lactamases (MβLs) including L1 has grown into an emerging threat. To probe whether mercaptoacetate thioesters inhibiting L1 is a contribution of the thioester itself or its hydrolysate, ten mercaptoacetate thioesters 1-10 were synthesized, which specifically inhibited L1, exhibiting IC50 values ranging from 0.17 to 1.2 μM, and 8 was found to be the best inhibitor (IC50 = 0.17 μM). These thioesters restored the antim ...[more]

PMID: 30109005

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Project description: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.

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Dataset Information

Mercaptoacetate thioesters and their hydrolysate mercaptoacetic acids jointly inhibit metallo-?-lactamase L1.

Publications

Mercaptoacetate thioesters and their hydrolysate mercaptoacetic acids jointly inhibit metallo-β-lactamase L1.

Similar Datasets

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