Structure-Based Discovery of Substituted 4,5′-Bithiazoles as Novel DNA Gyrase Inhibitors

Abstract

Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N(2)-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallography, confirming our initial in silico binding model. Furthermore, the high resolution of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compounds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.

Antibacterial Resistance via Gyrb24 Targeting

“…This site is target for most known coumarins [19][20][21]. Four chemical groups are making the coumarin: L-noviose sugar, the 5-methylpyrrole-2-carboxylic acid, the 3-aminocoumarin ring, and the 4-hydroxy-3-isoprenylbenzoyl moiety [19,20].…”

“…Studies showed that both hydroxyl benzoate isopentenyl moiety and the 5′-methyl group of the noviose have a stabilization effect on the formation of the complex [19]. Planning of new compounds with more profound antibiotic activities include extended alkyl group at the 5′-position of the noviose sugar [19][20][21]. Thus, both methyl groups of the noviose sugar are contributing to the hydrophobic interactions with the following residues in the ATPase site: Ile 78 and Ile90.…”

“…Thus, both methyl groups of the noviose sugar are contributing to the hydrophobic interactions with the following residues in the ATPase site: Ile 78 and Ile90. The remaining 5-methylpyrrole ring is also involved in hydrophobic pocket formations within gyrB24 with the following interaction points Val43, Ala47, Val71, Ile78, Val120, and Val167 [19][20][21].…”

Escherichia coli Topoisomerase IV E Subunit and an Inhibitor Binding Mode Revealed by NMR Spectroscopy

“…Structure-based drug design is a powerful technique that has been used in the development of potent antibacterial inhibitors (7,24,25). Both GyrB and ParE are validated drug targets and have attracted much drug discovery efforts around them (26,27).…”

Antimicrobial, antioxidant, and cytotoxic activities of endhopitic fungi Chaetomium sp. isolated from Phyllanthus niruri Linn: in vitro and in silico studies

“…Ten of them were used as the representative target to study the molecular mechanism of 27 ligands of Chaetomium fungal endophyte from diverse plants [21][22][23][24][25][26][27]. On the other hand, the proteins being used as the target are methylerythritol phosphate cytidyltransferase (PDB 1I52) [28], maltose binding periplasmic protein (MBP; PDB 1JVY) [29], glutamine-fructose-6-phosphate aminotransferase (PDB 1MOS) [30], -aminobutyrate aminotransferase (PDB 1SZS) [31], DNA gyrase (PDB 4DUH) [32] , enoylreductase (PDB 1I30) [33] , isoleucyl t-RNA synthetase (PDB 1JZQ) [34], aspartate aminotransferase (PDB 1IX6) [35], acetylglutamate kinase (PDB 1OHA) [36], and peptidyl t-RNA hydroxylase (PDB 2PTH) [37]. Table 5 …”