Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123 Palermo, Italy.
Drug Sciences Department, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, via Taramelli 12, 27100 Pavia, Italy.
Bioorg Med Chem. 2019 Mar 1;27(5):721-728. doi: 10.1016/j.bmc.2019.01.010. Epub 2019 Jan 16.
New compounds able to counteract staphylococcal biofilm formation are needed. In this study we investigate the mechanism of action of pyrrolomycins, whose potential as antimicrobial agents has been demonstrated. We performed a new efficient and easy method to use microwave organic synthesis suitable for obtaining pyrrolomycins in good yields and in suitable amount for their in vitro in-depth investigation. We evaluate the inhibitory activity towards Sortase A (SrtA), a transpeptidase responsible for covalent anchoring in Gram-positive peptidoglycan of many surface proteins involved in adhesion and in biofilm formation. All compounds show a good inhibitory activity toward SrtA, having IC values ranging from 130 to 300 µM comparable to berberine hydrochloride. Of note compound 1d shows a good affinity in docking experiment to SrtA and exhibits the highest capability to interfere with biofilm formation of S. aureus showing an IC of 3.4 nM. This compound is also effective in altering S. aureus murein hydrolase activity that is known to be responsible for degradation, turnover, and maturation of bacterial peptidoglycan and involved in the initial stages of S. aureus biofilm formation.
需要新的能够对抗葡萄球菌生物膜形成的化合物。在这项研究中，我们研究了吡咯霉素的作用机制，已经证明了其作为抗菌剂的潜力。我们采用了一种新的高效、简便的微波有机合成方法，适用于获得吡咯霉素，产量高，数量适合对其进行深入的体外研究。我们评估了它们对 Sortase A（SrtA）的抑制活性，SrtA 是一种转肽酶，负责将许多参与粘附和生物膜形成的表面蛋白共价锚定在革兰氏阳性肽聚糖上。所有化合物对 SrtA 都表现出良好的抑制活性，IC 值范围为 130-300µM，与盐酸小檗碱相当。值得注意的是，化合物 1d 在 SrtA 的对接实验中表现出良好的亲和力，并显示出最高的干扰金黄色葡萄球菌生物膜形成的能力，IC 为 3.4nM。该化合物还能有效改变金黄色葡萄球菌黏肽水解酶的活性，该酶已知负责细菌肽聚糖的降解、周转和成熟，并参与金黄色葡萄球菌生物膜形成的初始阶段。
