Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Inorganica e Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy.
Curr Med Chem. 2012;19(6):831-44. doi: 10.2174/092986712799034824.
Zinc-containing enzymes, such as carbonic anhydrases (CAs) and metalloproteases (MPs) play critical functions in bacteria, being involved in various steps of their life cycle, which are important for survival, colonization, acquisition of nutrients for growth and proliferation, facilitation of dissemination, invasion and pathogenicity. The development of resistance to many classes of clinically used antibiotics emphasizes the need of new antibacterial drug targets to be explored. There is a wealth of data regarding bacterial CAs and zinc MPs present in many pathogenic species, such as Neisseria spp., Helycobacter pylori Escherichia coli, Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, Haemophilus influenzae, Listeria spp, Vibrio spp., Pseudomonas aeruginosa, Legionella pneumophila, Streptomyces spp., Clostridium spp., Enterococcus spp., etc. Some of these enzymes have been cloned, purified and characterized by crystallographic techniques. However, for the moment, few potent and specific inhibitors for bacterial MPs have been reported except for Clostridium histolyticum collagenase, botulinum and tetanus neurotoxin and anthrax lethal factor, which will be reviewed in this article. Bacteria encode α-,β-, and/or γ-CA families, but up to now only the first two classes have been investigated in some detail in different species. The α-CAs from Neisseria spp. and H. pylori as well as the β-class enzymes from E. coli, H. pylori, M. tuberculosis, Brucella spp., S. pneumoniae, S. enterica and H. influenzae have been cloned and characterized. The catalytic/inhibition mechanisms of these CAs are well understood as X-ray crystal structures are available for some of them, but no adducts of these enzymes with inhibitors have been characterized so far. In vitro and in vivo studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates have been reported. Only for Neisseria spp., H. pylori, B. suis and S. pneumoniae CAs it has been possible to evidence inhibition of bacterial growth in vivo. Thus, bacterial CAs and MPs represent at this moment very promising targets for obtaining antibacterials devoid of the resistance problems of the clinically used such agents but further studies are needed to validate these and other less investigated enzymes as novel drug targets.
含锌酶，如碳酸酐酶（CA）和金属蛋白酶（MP），在细菌中发挥着关键作用，参与其生命周期的各个步骤，这些步骤对细菌的生存、定殖、获取生长和增殖所需的营养物质、促进传播、入侵和致病性至关重要。许多临床使用的抗生素的耐药性的发展强调了需要探索新的抗菌药物靶点。目前有大量关于许多致病物种中细菌 CA 和锌 MP 的数据，如奈瑟氏菌属、幽门螺杆菌、大肠杆菌、结核分枝杆菌、布鲁氏菌属、肺炎链球菌、沙门氏菌、流感嗜血杆菌、李斯特菌属、弧菌属、铜绿假单胞菌、嗜肺军团菌、链霉菌属、梭菌属、肠球菌属等。其中一些酶已经通过晶体学技术进行了克隆、纯化和表征。然而，目前除了梭菌胶原酶、肉毒杆菌和破伤风神经毒素以及炭疽致死因子外，还没有报道其他具有强大和特异性的细菌 MP 抑制剂，本文将对此进行综述。细菌编码α-、β-和/或γ-CA 家族，但到目前为止，只有前两类在不同物种中进行了详细研究。已经克隆和表征了来自奈瑟氏菌属和幽门螺杆菌的α-CA 以及来自大肠杆菌、幽门螺杆菌、结核分枝杆菌、布鲁氏菌属、肺炎链球菌、沙门氏菌和流感嗜血杆菌的β 类酶。这些 CA 的催化/抑制机制已经得到很好的理解，因为已经有一些它们的 X 射线晶体结构，但到目前为止，还没有这些酶与抑制剂的加合物被表征。已经报道了各种抑制剂，如阴离子、磺胺类和磺胺酸盐的体外和体内研究。只有在奈瑟氏菌属、幽门螺杆菌、猪布鲁氏菌和肺炎链球菌 CA 中，才有可能证明体内细菌生长的抑制作用。因此，细菌 CA 和 MPs 目前是获得无临床使用抗生素耐药性问题的抗菌药物的非常有前途的靶点，但需要进一步研究来验证这些和其他研究较少的酶作为新的药物靶点。
