Chemical Approach for Investigation of the Structure-Activity Relationship of Salmycin and Identification of a Glycan-based Analogue for Drug Resistant Staphylococcus aureus

New synthetic routes were devised for total synthesis of Fe³⁺-bound (ferri−) salmycin B (Sal B) (1), glycan-based Sal analogues 2–5 and their Fe³⁺-unbound (desferri−) counterparts 1′–5′ for the structure to activity relationship (SAR) study. The results of SAR study reveal the effective structure of 1 and its desferri-counterpart 1′ that are responsible for the observed inhibitory activity against Staphylococcus aureus (S. aureus). Among the analogues 2–5 and 2′–5′, glucose-based analogue 2 and its desferri-counterpart 2′ exhibited inhibitory potency comparable to 1 and 1′. Chemical modification of 2′ for further antibacterial study enabled us to discover desferri-Sal analogue 7′ that endowed with a simpler pharmacophore structure but significantly higher antibacterial potency against methicillin-sensitive and resistant S. aureus than the natural product 1′ and even the clinical vancomycin. Together with a better hydrolytic stability and shorter synthetic route, the analogue 7′ represents an attractive antibiotic lead for further exploration.