Discovering a new class of antifungal agents that selectively inhibits microbial carbonic anhydrases

Journal of Enzyme Inhibition and Medicinal Chemistry

Marco Pieroni¹  Gabriele Costantino¹  Giannamaria Annunziato¹  Marialaura Pavone¹  Agostino Bruno²  Laura Giovati³  Walter Magliani³  Stefania Conti³  Andrea Angeli⁴  Sonia Del Prete⁴  Claudiu T. Supuran⁴  Clemente Capasso⁵ 

[1] Department of Food and Drugs, University of Parma, Parma, Italy;Department of Food and Drugs, University of Parma, Parma, Italy;Experimental Therapeutics Program, IFOM the FIRC Institute for Molecular Oncology Foundation, Milano, Ital;Department of Medicine and Surgery, Ospedale Maggiore di Parma, University of Parma, Parma, Italy;Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy;National Council of Research (CNR), Istituto di Bioscenze e Biorisorse, Napoli, Italy;

关键词: Carbonic anhydrase inhibitors;    antimicrobial resistance;    drug design;    drug discovery;    antifungal agents;   

DOI  :  10.1080/14756366.2018.1516652

来源: publisher

【 摘 要 】

Infections caused by pathogens resistant to the available antimicrobial treatments represent nowadays a threat to global public health. Recently, it has been demonstrated that carbonic anhydrases (CAs) are essential for the growth of many pathogens and their inhibition leads to growth defects. Principal drawbacks in using CA inhibitors (CAIs) as antimicrobial agents are the side effects due to the lack of selectivity toward human CA isoforms. Herein we report a new class of CAIs, which preferentially interacts with microbial CA active sites over the human ones. The mechanism of action of these inhibitors was investigated against an important fungal pathogen, Cryptococcus neoformans, revealing that they are also able to inhibit CA in microbial cells growing in vitro. At our best knowledge, this is the first report on newly designed synthetic compounds selectively targeting β-CAs and provides a proof of concept of microbial CAs suitability as an antimicrobial drug target.

【 授权许可】

CC BY