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

ACS Infectious Diseases
Christian SchnaarsOve Alexander Høgmoen Åstrand

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...Continue Reading

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Citations

May 5, 2020·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Luigi PrincipeStefano Di Bella
Jun 4, 2020·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Smriti SharmaInshad Ali Khan
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Dec 8, 2020·Journal of Inorganic Biochemistry·Luana La PianaGraziella Vecchio
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Nov 14, 2018·ACS Infectious Diseases·Pasquale LincianoDonatella Tondi
Apr 17, 2020·ACS Infectious Diseases·Abigail C JacksonKatherine J Franz

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