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Amino Acid Thioester Derivatives: A Highly Promising Scaffold for the Development of Metallo-?-lactamase L1 Inhibitors.

ABSTRACT: In light of the biomedical significance of metallo-?-lactamases (M?Ls), ten new mercaptoacetic acid thioester amino acid derivatives were synthesized and characterized. Biological activity assays indicated that all these synthesized compounds are very potent inhibitors of L1, exhibiting an IC50 value range of 0.018-2.9 ?M and a K i value range of 0.11-0.95 ?M using cefazolin as substrate. Partial thioesters also showed effective inhibitory activities against NDM-1 and ImiS with an IC50 value range of 12-96 and 3.6-65 ?M, respectively. Also, all these thioesters increased susceptibility of E. coli cells expressing L1 to cefazolin, indicated by a 2-4-fold reduction in MIC of the antibiotic. Docking studies revealed potential binding modes of the two most potent L1 inhibitors to the active site in which the carboxylate group interacts with both Zn(II) ions and Ser221. This work introduces a highly promising scaffold for the development of metallo-?-lactamase L1 inhibitors.

SUBMITTER: Liu XL

PROVIDER: S-EPMC4468392 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Amino Acid Thioester Derivatives: A Highly Promising Scaffold for the Development of Metallo-β-lactamase L1 Inhibitors.

Liu Xiao-Long XL Shi Ying Y Kang Joon S JS Oelschlaeger Peter P Yang Ke-Wu KW

ACS medicinal chemistry letters 20150423 6

In light of the biomedical significance of metallo-β-lactamases (MβLs), ten new mercaptoacetic acid thioester amino acid derivatives were synthesized and characterized. Biological activity assays indicated that all these synthesized compounds are very potent inhibitors of L1, exhibiting an IC50 value range of 0.018-2.9 μM and a K i value range of 0.11-0.95 μM using cefazolin as substrate. Partial thioesters also showed effective inhibitory activities against NDM-1 and ImiS with an IC50 value ran ...[more]

PMID: 26101570

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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.

Project description:Metallo-?-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-?-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available ?-lactams are thus imperative. We investigated a zinc-chelating moiety, 1,4,7-triazacyclononane (TACN), for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae MICs, minimum bactericidal concentrations (MBCs), the serum effect, fractional inhibitory concentration indexes, and time-kill kinetics were determined using broth microdilution techniques according to Clinical and Laboratory Standards Institute (CSLI) guidelines. Enzyme kinetic parameters and the cytotoxic effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from between 8 and 64?mg/liter to 0.03?mg/liter in the presence of TACN. The TACN-meropenem combination showed bactericidal effects with an MBC/MIC ratio of ?4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be noncytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active-site pockets. This was supported by its inhibition constant (Ki ), which was 0.044??M, and its inactivation constant (K inact), which was 0.0406 min-1, demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor.IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported to be critical in the World Health Organization's priority pathogens list for the research and development of new antibiotics. CRE produce enzymes, such as metallo-?-lactamases (MBLs), which inactivate ?-lactam antibiotics. Combination therapies involving a ?-lactam antibiotic and a ?-lactamase inhibitor remain a major treatment option for infections caused by ?-lactamase-producing organisms. Currently, no MBL inhibitor-?-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the activity of carbapenem. This study demonstrates that TACN inhibits MBLs efficiently and holds promises as a potential MBL inhibitor to help curb the global health threat posed by MBL-producing CREs.

Dataset Information

Amino Acid Thioester Derivatives: A Highly Promising Scaffold for the Development of Metallo-?-lactamase L1 Inhibitors.

Publications

Amino Acid Thioester Derivatives: A Highly Promising Scaffold for the Development of Metallo-β-lactamase L1 Inhibitors.

Similar Datasets

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