Zhang et al. hypothesized that a structurally similar disaccharide, GlcNAc-1,6-anhydro-MurNAc, could be a minimal moiety that acts as a competitive inhibitor to lipid II and lacks a reducing end for glycan chain elongation. The authors developed a 15-step total synthesis of the disaccharide-pentapeptide unit, called compound 1, and the disaccharide-only compound, 1-deAA. They incubated compound 1 with lipid II from Staphylococcus aureus, the TGase SgtB and the transpeptidase PBP4, which crosslinks the peptides in peptidoglycan. Liquid chromatography—high-resolution mass spectrometry analysis of the product showed that compound 1 was properly processed by these enzymes. Further, 1-deAA was also able to incorporate into SgtB.

The team found that S. aureus treated with 1-deAA had peptidoglycan strands with shorter glycan lengths; however, high concentrations of 1-deAA (in the range of 400–800 μM) were needed to reduce the glycan content by at least 60%. 1-deAA also showed synergy with the transpeptidase inhibitor vancomycin, lowering its minimum inhibitory concentration in S. aureus by half, although this again required a high concentration of 1-deAA. Although 1-deAA still needs to be optimized, Zhang et al. have shown the potential for carbohydrate-based TGase inhibitors.