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Synthesis and Preclinical Evaluation of TPA-Based Zinc Chelators as Metallo-β-lactamase Inhibitors
- Source :
- ACS Infectious Diseases, ACS Infectious Diseases, American Chemical Society, 2018, ⟨10.1021/acsinfecdis.8b00137⟩
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
Abstract
- The rise of antimicrobial resistance (AMR) worldwide and the increasing spread of multi-drug-resistant organisms expressing metallo-β-lactamases (MBL) require the development of efficient and clinically available MBL inhibitors. At present, no such inhibitor is available, and research is urgently needed to advance this field. We report herein the development, synthesis, and biological evaluation of chemical compounds based on the selective zinc chelator tris-picolylamine (TPA) that can restore the bactericidal activity of Meropenem (MEM) against Pseudomonas aeruginosa and Klebsiella pneumoniae expressing carbapenemases Verona integron-encoded metallo-β-lactamase (VIM-2) and New Delhi metallo-β-lactamase 1 (NDM-1), respectively. These adjuvants were prepared via standard chemical methods and evaluated in biological assays for potentiation of MEM against bacteria and toxicity (IC50) against HepG2 human liver carcinoma cells. One of the best compounds, 15, lowered the minimum inhibitory concentration (MIC) of MEM by a factor of 32-256 at 50 μM within all tested MBL-expressing clinical isolates and showed no activity toward serine carbapenemase expressing isolates. Biochemical assays with purified VIM-2 and NDM-1 and 15 resulted in inhibition kinetics with kinact/ KI of 12.5 min-1 mM-1 and 0.500 min-1 mM-1, respectively. The resistance frequency of 15 at 50 μM was in the range of 10-7 to 10-9. 15 showed good tolerance in HepG2 cells with an IC50 well above 100 μM, and an in vivo study in mice showed no acute toxic effects even at a dose of 128 mg/kg.
- Subjects :
- 0301 basic medicine
Pyridines
Klebsiella pneumoniae
Drug Evaluation, Preclinical
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
Microbial Sensitivity Tests
medicine.disease_cause
Meropenem
beta-Lactamases
Microbiology
03 medical and health sciences
Minimum inhibitory concentration
Bacterial Proteins
In vivo
medicine
Humans
Bioassay
Pseudomonas Infections
IC50
ComputingMilieux_MISCELLANEOUS
Chelating Agents
biology
[CHIM.ORGA]Chemical Sciences/Organic chemistry
Pseudomonas aeruginosa
Chemistry
bacterial infections and mycoses
biology.organism_classification
[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Anti-Bacterial Agents
Klebsiella Infections
3. Good health
Zinc
030104 developmental biology
Infectious Diseases
Drug Design
Toxicity
beta-Lactamase Inhibitors
medicine.drug
Subjects
Details
- ISSN :
- 23738227
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- ACS Infectious Diseases
- Accession number :
- edsair.doi.dedup.....06a99720e5a1149d53c0d780d8118c69