Carbacaprazamycins, which are chemically stable analogues of caprazamycins, were designed and synthesized. These analogues were active against drug-resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and their activities were comparable to those of the parent caprazamycins. The effect of treatment with carbacaprazamycin on morphological changes in S. aureus indicated that the mode of action was completely different from those of existing peptidoglycan inhibitors.

The continued emergence of drug-resistance to existing antibacterial agents represents a severe and ongoing public health concern, which demands the discovery of new antibiotics. However the number of novel classes of antibacterial drugs launched in the clinic has been remarkably slow since the 1960s, and it is urgent to develop novel antibacterial agents to fight against drug-resistant bacterial pathogens. Peptidoglycan is a component of the bacterial cell wall, which consists of a repeated N-acetylmuramic acid (MurNAc) and Nacetylglucosamine (GluNAc) polymer cross-linked with polypeptides, and is a good target for antibacterial drug discovery. Among enzymes responsible for its biosynthesis, phospho-MurNAc-pentapeptide translocase (MraY) is a novel and promising target. Many nucleoside natural products, which strongly inhibit MraY, have been found in nature. This review will summarize the synthesis and biological properties of selected MraY inhibitory nucleoside natural products and their analogues synthesized in our laboratory and by others.

Simplification of caprazamycins, which are promising antibacterial nucleoside natural products, was conducted by scaffold-hopping of the structurally complex diazepanone moiety to the isoxazolidine scaffold. The designed isoxazolidine-containing uridine derivatives were synthesized by an intramolecular 1,3-dipolar cycloaddition of alkenyl nitrone as a key step. The lactone-fused isoxazolidine intermediate was easily converted to the target compounds by sequential introduction of key substituents upon ring-opening the lactone moiety by nucleophilic substitution and electrophilic capping of the resulting primary alcohol. Several analogues exhibited good activity against H. influenzae ATCC 10211 (MIC 0.25-0.5 μg mL(-1)) and moderate activity against vancomycin-resistant E. faecalis SR7914 (MIC 4-8 μg mL(-1)).

Function‐oriented synthesis of a class of liponucleoside antibiotics was investigated through rational simplification guided by previous structure–activity relationship studies of caprazamycins and muraymycins to address the issue associated with their molecular complexity. A lactam‐fused isoxazolidine scaffold was designed, and a diverse set of lactam‐fused isoxazolidines derivatives were constructed by intramolecular 1,3‐dipolar cycloaddition of alkenyl nitrones. Several analogues exhibited moderate activity against a range of Gram‐positive drug‐resistant bacterial pathogens.