a Department of Food and Drugs , University of Parma , Parma , Italy.
b Department of Medicine and Surgery, Ospedale Maggiore di Parma , University of Parma , Parma , Italy.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):1537-1544. doi: 10.1080/14756366.2018.1516652.
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.
目前，可利用的抗菌治疗方法无法应对病原体耐药性导致的感染，这对全球公共健康构成了威胁。最近有研究表明，碳酸酐酶（CA）对许多病原体的生长至关重要，其抑制作用会导致生长缺陷。将碳酸酐酶抑制剂（CAI）作为抗菌药物使用的主要缺点是缺乏对人源 CA 同工型的选择性，从而导致副作用。在此，我们报告了一类新型 CAI，其优先与微生物 CA 的活性位点相互作用，而不是与人源 CA 同工型相互作用。我们针对一种重要的真菌病原体新型隐球菌研究了这些抑制剂的作用机制，结果表明它们还能够抑制体外生长的微生物细胞中的 CA。据我们所知，这是首次报道专门针对β-CA 的新型设计合成化合物，为微生物 CA 作为抗菌药物靶点的适用性提供了概念验证。
