Synthesis and Preclinical Evaluation of TPA-Based Zinc Chelators as Metallo-β-lactamase Inhibitors

• Published in: ACS infectious diseases 2018-09, Vol.4 (9), p.1407-1422
• Main Authors: Schnaars, Christian, Kildahl-Andersen, Geir, Prandina, Anthony, Popal, Roya, Radix, Sylvie, Le Borgne, Marc, Gjøen, Tor, Andresen, Adriana Magalhães Santos, Heikal, Adam, Økstad, Ole Andreas, Fröhlich, Christopher, Samuelsen, Ørjan, Lauksund, Silje, Jordheim, Lars Petter, Rongved, Pål, Åstrand, Ove Alexander Høgmoen
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Bacteriology; beta-Lactamase Inhibitors - chemical synthesis; beta-Lactamase Inhibitors - chemistry; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases - chemistry; beta-Lactamases - metabolism; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacology; Chemical Sciences; Drug Design; Drug Evaluation, Preclinical; Humans; Klebsiella Infections - microbiology; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - enzymology; Klebsiella pneumoniae - genetics; Klebsiella pneumoniae - metabolism; Life Sciences; Medicinal Chemistry; Meropenem - pharmacology; Microbial Sensitivity Tests; Microbiology and Parasitology; Organic chemistry; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - enzymology; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - metabolism; Pseudomonas Infections - microbiology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Zinc - chemistry; Zinc - metabolism
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.8b00137

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 k inact/K I 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.