Cascioferro Stella, Totsika Makrina, Schillaci Domenico
Department of Biological, Chemical and Pharmaceutical Science and Technology, Università degli Studi di Palermo, Via Archirafi 32, Palermo, Italy.
Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, QLD 4059, Australia.
Microb Pathog. 2014 Dec;77:105-12. doi: 10.1016/j.micpath.2014.10.007. Epub 2014 Oct 18.
Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance.
分选酶A是一种膜酶，负责将表面暴露的蛋白质锚定到革兰氏阳性菌的细胞壁包膜上。作为分选酶亚家族中一个经过充分研究的成员，它催化重要毒力因子锚定到葡萄球菌、肠球菌和链球菌表面，在革兰氏阳性菌的致病过程中发挥关键作用。因此，它被认为是开发新型抗感染药物的一个有前景的靶点，这类药物旨在干扰重要的革兰氏阳性菌毒力机制，如与宿主组织的黏附、逃避宿主防御和生物膜形成。分选酶A作为一种革兰氏阳性菌生长或存活不需要的酶，且位于细胞膜上，便于抑制剂靶向作用，这些额外特性进一步支持了分选酶A是抗毒力药物开发理想靶点的观点。迄今为止，通过对化合物库（合成或天然）进行高通量筛选或计算机筛选，已鉴定出许多分选酶A抑制剂。虽然许多已被证明是探究该酶作用模型的有用工具，但也有几种有望开发成为强效抑制剂。本综述聚焦于目前正在开发的最有前景的分选酶A抑制剂化合物，这些化合物有望成为一类新型抗感染药物的先导物，这类药物对于应对日益严重的抗菌药物耐药性问题至关重要。
