Anti-bacterial glycosyl triazoles – identification of anN-acetylglucosamine derivative with bacteriostatic activity againstBacillus

Abstract

N-acetylglucosaminidases (GlcNAcases) play an important role in the remodeling and recycling of bacterial peptidoglycan. Inhibitors of bacterial GlcNAcases can serve as antibacterial agents and provide an opportunity for the development of new antibiotics. We report the synthesis of triazole derivatives of N-acetylglucosamine using a copper promoted azide-alkyne coupling reaction between 1-azido-N-acetylglucosamine and a small library of terminal alkynes prepared via the Ugi reaction. These compounds were evaluated for their ability to inhibit the growth of bacteria. Two compounds that show bacteriostatic activity against Bacillus were identified, with MIC values of approximately 60 μM in both cases. Bacillus subtilis cultured in the presence of sub-MIC amounts of the glycosyl triazole inhibitors exhibit an elongated phenotype characteristic of impaired cell division. This represents the first report of inhibitors of bacterial cell wall GlcNAcases that demonstrate inhibition of cell growth in whole cell assays.

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

“…13 We suggested at the time that the likely target of the glycosyl triazole was an exo - acting GlcNAcase, most likely LytG, the major active autolytic GlcNAcase from B. subtilis . 11 Using a PG hydrolysis assay, we have found that the diamides fgka (5) and fgkc (21) inhibit LytG activity.…”

“…13 Preliminary studies suggested that the bacterial target of BI.fgba was an exo acting GlcNAcase, and cells treated with BI.fgba exhibited the elongated and linked phenotype characteristic of disrupted autolysin activity. 4,8,14,15,16 Our preliminary studies indicated that the aglycone of BI.fgba possessed only a 2-fold weaker minimum inhibitory concentration (MIC) (125 µM) (data not shown).…”

Peptidoglycan pathways: there are still more!

“…This approach resulted in some compounds with good IC 50 values (the concentration of an inhibitor where the response (or binding) is reduced by half) on an in vitro scale; however, they did not show in vivo activity, such as in the case of compound 2. 21,[31][32][33][34] The second try was to directly mimic lipid II 35 or ring F of the moenomycin, 36 which resulted in low to moderate activity compounds like compound 3 with an MIC (minimum inhibitory concentration) of 60 mM against Bacillus cereus. 35 Additionally, several articles relied on HTS (high throughput screening) or in silico protocols to generate new leads.…”

“…21,[31][32][33][34] The second try was to directly mimic lipid II 35 or ring F of the moenomycin, 36 which resulted in low to moderate activity compounds like compound 3 with an MIC (minimum inhibitory concentration) of 60 mM against Bacillus cereus. 35 Additionally, several articles relied on HTS (high throughput screening) or in silico protocols to generate new leads. Despite advances in obtaining novel leads with apparently potent in vitro activities, none of the tested new structures were efficient in in vivo models.…”

Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity

“…2b ). Attempts to mimic directly lipid II 31 , or the ring F of moenomycin 32 , with monosaccharide scaffolds gave compounds with only low to medium activity (MIC=60 μM against Bacillus cereus 31 ). More recently, de novo inhibitors for GT discovered using high-throughput screening 33 34 35 or in silico methods 36 , were shown to have improved in vitro activity (MIC=0.25 μM against MRSA 33 ), but no in vivo activity.…”