TY - JOUR
T1 - Discovery of Sortase A covalent inhibitors with benzofuranene cyanide structures as potential antibacterial agents against Staphylococcus aureus
AU - Lei, Shuwen
AU - Hu, Yang
AU - Yuan, Chang
AU - Sun, Ran
AU - Wang, Juntao
AU - Zhang, Yong
AU - Zhang, Yang
AU - Lu, Dan
AU - Fu, Lei
AU - Jiang, Faqin
N1 - Funding Information:
We appreciate the financial support of National Key R & D Plan "blue granary science and technology innovation” ( 2019YFD0901902 ), Medicine and Engineering Interdisciplinary Research Fund of Shanghai Jiao Tong University ( YG2017MS77 ), Xiamen Blue Bay Science & Technology Co. Ltd , and Leto laboratories co. Ltd.
Publisher Copyright:
© 2021 Elsevier Masson SAS
PY - 2022/2/5
Y1 - 2022/2/5
N2 - Sortase A (SrtA) is a cysteine transpeptidase of most gram-positive bacteria that is responsible for the anchoring of many surface protein virulence factors to the cell wall. SrtA ablation has demonstrated to alleviate the infection without affecting the viability of bacteria. Herein, a series of benzofuran cyanide derivatives were synthesized and evaluated. Several compounds exhibited excellent inhibitory activity against SrtA with IC50 values from 3.3 μM to 21.8 μM compared with the known SrtA inhibitor pHMB (IC50 = 130 μM). Ⅲ-1, Ⅲ-15, Ⅲ-34 and V-1 showed potent inhibitory effects on biofilm formation with IC50 values from 2.1 μM to 54.2 μM. Invasion assays showed the four compounds caused a decrease of 4%–24.0% in the uptake of the S. aureus strain by 293T cells. Further assay showed that compound Ⅲ-15 decreased the amount of cell wall-associated protein A by 26.5%. Structure-activity relationship and docking studies demonstrated that the acrylonitrile moiety of the compounds played an important role in enhancing the activity. When the double bond of acrylonitrile changed to single bond, the activity was decreased significantly. This indicates that acrylonitrile, which is a Michael receptor, can inhibit the activity of SrtA by covalent binding effectively to the thiol group of Cys184.
AB - Sortase A (SrtA) is a cysteine transpeptidase of most gram-positive bacteria that is responsible for the anchoring of many surface protein virulence factors to the cell wall. SrtA ablation has demonstrated to alleviate the infection without affecting the viability of bacteria. Herein, a series of benzofuran cyanide derivatives were synthesized and evaluated. Several compounds exhibited excellent inhibitory activity against SrtA with IC50 values from 3.3 μM to 21.8 μM compared with the known SrtA inhibitor pHMB (IC50 = 130 μM). Ⅲ-1, Ⅲ-15, Ⅲ-34 and V-1 showed potent inhibitory effects on biofilm formation with IC50 values from 2.1 μM to 54.2 μM. Invasion assays showed the four compounds caused a decrease of 4%–24.0% in the uptake of the S. aureus strain by 293T cells. Further assay showed that compound Ⅲ-15 decreased the amount of cell wall-associated protein A by 26.5%. Structure-activity relationship and docking studies demonstrated that the acrylonitrile moiety of the compounds played an important role in enhancing the activity. When the double bond of acrylonitrile changed to single bond, the activity was decreased significantly. This indicates that acrylonitrile, which is a Michael receptor, can inhibit the activity of SrtA by covalent binding effectively to the thiol group of Cys184.
KW - Antibacterial effect
KW - Benzofuranyl cyanide
KW - Covalent inhibitor
KW - Sortase A
KW - Staphylococcus aureus
UR - http://www.scopus.com/inward/record.url?scp=85121592606&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2021.114032
DO - 10.1016/j.ejmech.2021.114032
M3 - Article
C2 - 34954590
AN - SCOPUS:85121592606
SN - 0223-5234
VL - 229
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114032
ER -