Infection and Drug Resistance (Jul 2019)
Indole-core-based novel antibacterial agent targeting FtsZ
Abstract
Wenchang Yuan,*,1 Zhiwu Yu,*,2 Weiqi Song,*,3 Yanan Li,4 Zhiyuan Fang,1 Baizhen Zhu,1 Xiaomei Li,1 Hao Wang,5 Wei Hong,6 Ning Sun1,71The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, People’s Republic of China; 2Division of Laboratory Science, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, People’s Republic of China; 3School of Public Health, Guangzhou Medical University, Guangzhou 511436, People’s Republic of China; 4Department of Pharmacy, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, People’s Republic of China; 5School of Pharmacy, Ningxia Medical University, Yinchuan 750004, People’s Republic of China; 6School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan 750021, People’s Republic of China; 7State Key Laboratory of Chemical Biology and Drug Discovery, and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, People’s Republic of China*These authors contributed equally to this workBackground: The prevalence of drug-resistant bacterial infections urges the development of new antibacterial agents that possess a mechanism of action different from traditional antibiotics. FtsZ has been recognized as a key functional protein in bacterial cell division and it is currently believed to be a potential target for the development of novel antibacterial agents.Purpose: The primary aim of the study is to screen out an inhibitor targeting at FtsZ and followed to investigate its antibacterial activity and mode of action.Methods: Cell-based cell division inhibitory screening assay, antimicrobial susceptibility test, minimum bactericidal concentration assay, time-killing curve determination, FtsZ polymerization assay, GTPase activity assay, and molecular modeling were performed in the present study.Results: The screening study from a small library consisting of benzimidazole and indole derivatives discovered a compound (CZ74) with an indole-core structure. The compound exhibited strong cell division inhibitory effect. In addition, CZ74 shows high antibacterial potency against a number of tested Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. The minimum inhibitory concentration values obtained were within the range of 2–4 μg/mL. The results of biological study revealed that CZ74 at 2 μg/mL is able to disrupt FtsZ polymerization and inhibit GTPase activity and cell division. From molecular modeling study, CZ74 is found possibly binding into the interdomain cleft of FtsZ protein and then leads to inhibitory effects.Conclusion: This indole-cored molecule CZ74 could be a potential lead compound and could be further developed as a new generation of antibacterial agents targeting FtsZ to combat against multidrug-resistant bacteria.Keywords: indole-core-based derivative, antibacterial, cell division, FtsZ, antibiotic resistant
