Design and synthesis of quinolinium-based derivatives targeting FtsZ for antibacterial evaluation and mechanistic study

Dong Xiao Zhong, Meng Ting She, Xiao Chun Guo, Bo Xin Zheng, Xuan He Huang, Yi Han Zhang, Hooi Leng Ser, Wing Leung Wong, Ning Sun, Yu Jing Lu

Research output: Journal article publicationJournal articleAcademic researchpeer-review

1 Citation (Scopus)

Abstract

The discovery of small molecular inhibitors targeting essential and conserved bacterial drug targets such as FtsZ protein is a promising approach to fight against multi-drug resistant bacteria. In the present study, two new series of FtsZ inhibitors based on a 1-methylquinolinium scaffold were synthesized. The inhibitors possess a variety of substituent groups including the cyclic or linear amine skeleton at the 2- and 4-position of the quinolinium ring for structure-activity relationship study. In general, the inhibitors bearing a cyclic amine substituent at the 4-position of the quinolinium ring showed better antibacterial activity (MIC down to 0.25 μg/mL) than that at the 2-position, especially against Gram-positive bacteria. Among the twenty FtsZ inhibitors examined in various assays, A3 was identified to exhibit excellent antibacterial activity against S. aureus (MIC = 0.5–1 μg/mL), S. epidermidis (MIC = 0.25 μg/mL) and E. faecium (MIC = 1–8 μg/mL). More importantly, A3 showed low hemolytic toxicity (IC5 = 64 μg/mL) and was found not readily to induce drug resistance. A3 at 2–8 μg/mL promoted the polymerization of FtsZ and interrupted the bacterial division. Furthermore, the ligand-FtsZ interaction study conducted with circular dichroism and molecular docking revealed that A3 induced secondary structure changes of FtsZ protein upon binding to the interdomain cleft of the protein. A3 is thus a potent inhibitor of FtsZ and shows potential to be used as a new antibacterial agent against drug-resistant bacteria.

Original languageEnglish
Article number114360
JournalEuropean Journal of Medicinal Chemistry
Volume236
DOIs
Publication statusPublished - 5 Jun 2022

Keywords

  • 1-Methylquinolinium derivatives
  • Antibacterial activity
  • Drug resistance
  • FtsZ inhibitor
  • Mechanism of action

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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