Diamide Inhibitors of the Bacillus subtilis N-Acetylglucosaminidase LytG That Exhibit Antibacterial Activity

Abstract

N-acetylglucosaminidases (GlcNAcases) play an important role in the remodeling and recycling of bacterial peptidoglycan by degrading the polysaccharide backbone. Genetic deletions of autolysins can impair cell division and growth, suggesting an opportunity for using small molecule autolysin inhibitors as both tools for studying the chemical biology of autolysins and also serving as anti-bacterial agents. We report here the synthesis and evaluation of a panel of diamides that inhibit the growth of Bacillus subtilis. Two compounds, fgkc (5) and fgka (21), were found to be potent inhibitors (MIC 3.8 ± 1.0 and 21.3 ± 0.1 µM respectively). These compounds inhibit the B. subtilis family 73 glycosyl hydrolase LytG, an exo GlcNAcase. Phenotypic analysis of fgkc (21)-treated cells demonstrate a propensity for cells to form linked chains, suggesting impaired cell growth and division.

Metabolic inhibitors of bacterial glycan biosynthesis

“…Although systematic efforts to screen for inhibitors of glycan biosynthesis have been undertaken in mammalian systems, [71][72][73][74] there is a relative paucity of bacterial glycosylation inhibitors. The progress that has been made in this area has relied on indepth characterization of glycosyltransferases, [75][76][77][78] information that is oen a rate-limiting step in inhibitor development. As an alternative to direct screening of glycosyltransferases, Vocadlo, 42 Paulson 44 and others 21,45 have demonstrated the potential of unnatural monosaccharides or glycosides bearing key structural features (e.g.…”

Asymmetric phosphoric acid–catalyzed four-component Ugi reaction

“…It has facilitated rapid access to diverse libraries of biologically important molecules because of its ease of synthetic operation (Fig. 1B) (2)(3)(4)(5)(6). In industrial applications, Dömling and co-workers reported an elegant two-step multicomponent synthesis of praziquantel, a drug to treat the parasitical disease schistosomiasis, via Ugi-cyclization cascade (Fig.…”

Synthesis and Cytotoxic Analysis of Novel Myrtenyl Grafted Pseudo-Peptides Revealed Potential Candidates for Anticancer Therapy

“…The well-known Ugi four-component reaction [31,32] (Ugi-4CR), which comprises an acid, an amine, an isocyanide, and carbonyl compound, is further employed for a diverse-oriented synthesis with an application for developing potential drugs [33][34][35][36][37]. Based on the advantages known for the Ugi-4CR [38], we selected this reaction for the one-pot assembly of Myrtenyl derivatives 1a-c and 2a-c (Scheme 1).…”