Identification of a New Class of FtsZ Inhibitors by Structure-Based Design and in Vitro Screening

Abstract

The Filamenting temperature-sensitive mutant Z (FtsZ), an essential GTPase in bacterial cell division, is highly conserved among Gram-positive and Gram-negative bacteria and thus considered an attractive target to treat antibiotic-resistant bacterial infections. In this study, a new class of FtsZ inhibitors bearing the pyrimidine-quinuclidine scaffold was identified from structure-based virtual screening of natural product libraries. Iterative rounds of in silico studies and biological evaluation established the preliminary structure-activity relationships of the new compounds. Potent FtsZ inhibitors with low micromolar IC₅₀ and antibacterial activity against S. aureus and E. coli were found. These findings support the use of virtual screening and structure-based design for the rational development of new antibacterial agents with innovative mechanisms of action.

Understanding Nucleotide-Regulated FtsZ Filament Dynamics and the Monomer Assembly Switch with Large-Scale Atomistic Simulations

“…FtsZ has been validated as the target of the in vivo effective antibacterial compound PC190723 (7), which modulates FtsZ assembly by stabilizing its polymers (8,9) and binds into the cleft between the C-terminal domain and the core helix H7 of this protein (9)(10)(11). Moreover, several nucleotide analogs (12,13) and nonnucleotide compounds that selectively target the nucleotide site of FtsZ have also been identified (14)(15)(16).…”

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

“…The screening generated compound 28 which displays significantly activity improvement in the biological tests. The GTPase inhibitory effect (IC 50 37.5 μM) and antibacterial activity against S. aureus (MIC 24.6 μM) and E. coli (MIC 49.6 μM) of 28 were more than 10 times higher compared to that of 27 [100]. In addition, these derivatives were reported to selectively inhibit FtsZ over tubulin and restore susceptibility of MRSA (ATCC BAA-41) to β-lactam antibiotics [101].…”

“…To identify hit compounds targeting at the GTP binding site of FtsZ, Wong and co-workers carried out a structure-based virtual screening of over 20,000 compounds, which contain natural products and their semisynthetic derivatives using the crystal structure of Methanococcus jannaschii FtsZ [100]. The ten top-ranked compounds from the screening were further tested for their GTPase inhibitory effect in vitro and antibacterial activity against pathogens.…”

Lessons from bacterial homolog of tubulin, FtsZ for microtubule dynamics

“…Several compounds have been identified that target the GTP-binding site of FtsZ and thereby inhibit polymerization (Läppchen et al 2008, Chan et al 2013, Ruiz-Avila et al 2013, Panda et al 2016. A study using GTP analogs established several molecules to have potent anti-FtsZ activity, while some among them showed differential effects on tubulin activity (Läppchen et al 2008).…”

“…Another study used structure-based virtual screening to identify natural pyrimidine-substituted quinuclidines as FtsZ inhibitors (Chan et al 2013). Using induced fit docking analysis, it was predicted that some of these compounds mimicked GTP and were able to establish key interactions within the triphosphate, sugar and nucleotide-binding regions of FtsZ (Chan et al 2013). …”