mraY-inhibiting sphaerimicin analogues for drug-resistant bacteria

Simplified analogues of sphaerimicins — complex macrocyclic natural products that inhibit mraY, a bacterial membrane enzyme required for cell wall synthesis — could help treat drug-resistant bacterial infections.

Molecular modeling, design and retrosynthetic analysis led to the chemical synthesis of simplified sphaerimicin analogues with antibacterial activity against Gram-positive drug-resistant pathogens, and structural analysis of one of these analogues bound to mraY supported a structure-based design and optimization process that yielded a sphaerimicin analogue with a macrocyclic core that inhibited mraY with an IC₅₀ of 41 nM...