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

• Published in: mBio Vol. 11; no. 2
• Main Authors: Wachino, Jun-Ichi, Jin, Wanchun, Kimura, Kouji, Kurosaki, Hiromasa, Sato, Ayato, Arakawa, Yoshichika
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 17.03.2020
• Subjects: Acinetobacter - drug effects; Animals; Anti-Bacterial Agents - pharmacology; beta-Lactamase Inhibitors - chemical synthesis; beta-Lactamase Inhibitors - pharmacology; carbapenems; Carbapenems - pharmacology; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Cell Line; CRE; Drug Discovery; Drug Resistance, Bacterial; Enterobacteriaceae - drug effects; Escherichia coli - drug effects; Humans; Male; Meropenem - pharmacology; metallo-β-lactamase; Mice; Microbial Sensitivity Tests; Microsomes, Liver - drug effects; Pseudomonas aeruginosa - drug effects; sulfamoyl heteroarylcarboxylic acids; Therapeutics and Prevention; carbapenems; sulfamoyl heteroarylcarboxylic acids; metallo-β-lactamase; CRE
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.03144-19

Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant (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 to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing spp. and engineered 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 Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing and dually NDM-1/VIM-1-producing 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. Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including However, carbapenem-resistant (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.