Discovery of Anti-TB Agents that Target the Cell-Division Protein FtsZ

Abstract

The emergence of multidrug-resistant Mycobacterium tuberculosis strains has made many of the currently available anti-tuberculosis (TB) drugs ineffective. Accordingly, there is a pressing need to identify new drug targets. Filamentous temperature-sensitive protein Z (FtsZ), a bacterial tubulin homologue, is an essential cell-division protein that polymerizes in a GTP-dependent manner, forming a highly dynamic cytokinetic ring, designated as the Z ring, at the septum site. Other cell-division proteins are recruited to the Z ring and, upon resolution of the septum, two daughter cells are produced. Since inactivation of FtsZ or alteration of FtsZ assembly results in the inhibition of Z-ring and septum formation, FtsZ is a very promising target for novel antimicrobial drug development. This review describes the function and dynamic behaviors of FtsZ and the recent development of FtsZ inhibitors as potential anti-TB agents.

In vitro–in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacterium tuberculosis

“…8, 9 Importantly, this affords the opportunity to use known pharmacophores such as, pyridopyrazine, pteridine and benzimidazole, as starting points for SAR optimization. 6, 7 Specifically, selected 2,5,6- and 2,5,7-trisubstituted benzimidazoles developed through rational drug design, have demonstrated potency with low or negligible cytotoxicity. 9 …”

Identification of Agents Targeting Ftsz Assembly

“…A number of the compounds were found to exhibit antituberculosis activity and subsequently a further series of compounds were screened for their activity against drug-resistant and drug-sensitive M. tuberculosis strains [100,101], with SB-RA-2001 17 ( Figure 5 & Table 1) identified as an effective antitubercular agent.…”

Drug discovery targeting cell division proteins, microtubules and FtsZ

“…121–123 As FtsZ and tubulin have close functional homology, 124–126 compounds that are known to inhibit or stabilize tubulin/microtubules can serve as a good starting point for the discovery and development of novel antibacterial agents. 122, 123, 127–129 After modifications, these tubulin inhibitors can be made specific to target FtsZ with no appreciable cytotoxicity to eukaryotic cells. Although drug development in this field is still in an early stage, several classes of compounds have been found effective against Mtb FtsZ and a number of compounds have been identified as promising leads.…”