Identification of anti-tuberculosis agents that target the cell-division protein FtsZ.

Yuan Lin,Jiandong Jiang,Yanxing Han,Ningyu Zhu,Shuyi Si

doi:10.1038/ja.2014.89

Abstract

Antibiotic resistance to Mycobacterium tuberculosis is a growing problem. Therefore, development of new anti-tuberculosis antibiotics is urgent for the control of tuberculosis (TB) infections. FtsZ, the homolog of eukaryotic tubulin, is a GTPase that assembles into cytokinetic Z rings essential for cell division in prokaryotic cells. FtsZ (filamentous temperature-sensitive protein Z) polymerizes in a GTP-dependent manner, and polymerization of FtsZ forms into dynamic protofilaments. In this study, we screened 20,000 compounds to identify inhibitors of GTPase activity of M. tuberculosis FtsZ. We found that 297F inhibited GTPase and polymerization of FtsZ, and reduced the amount of FtsZ polymers. Furthermore, 297F has anti-TB activity with low cytotoxicity and shows no antibacterial activities toward other Gram-positive or Gram-negative strains. In vitro, 297F also induced filamentation in Mycobacterium smegmatis. All results suggest that 297F inhibits bacterial proliferation by targeting M. tuberculosis FtsZ and it may be useful as a lead compound for developing anti-TB agents.

Highlights

Tuberculosis (TB) is a common infectious disease that claims about 2 million lives worldwide
HIV epidemics combined with the emergence of multidrug-resistant (MDR-TB) and extensive-resistant (XDR-TB) have aggravated a TB resurgence.[1]
GTPase activity assay of FtsZ FtsZ is known to have GTPase activity, we measured the activity of the M. tuberculosis FtsZ used in this study

Summary

Introduction

Tuberculosis (TB) is a common infectious disease that claims about 2 million lives worldwide. FtsZ (filamentous temperature-sensitive protein Z) is a protein key to bacterial cell-division protein. It is present in almost all prokaryotes and is the homolog of tubulin in eukaryotes.[2] FtsZ shares only 10% of its sequence identity at the protein level with tubulin. GTP hydrolysis and polymerization of FtsZ have been shown to be at the root of the Z-ring dynamics.[5,6] The recruitment of several other cell-division proteins leads to Z-ring contraction, resulting in septum formation and eventually cell division. In the absence of FtsZ, bacterial cell division is inhibited, DNA replication and nucleoid segregation occur normally. Such a condition leads to a filamentous phenotype and eventually cell death. FtsZ is an especially promising target for new antimicrobial drugs because of its central role in bacterial cell division.[7]

Methods

Results

Conclusion