Characterization of compound A, a novel lincomycin derivative active against methicillin-resistant Staphylococcus...

Methicillin-resistant Staphylococcus aureus (MRSA) is one of causative bacteria for hospital- and community-acquired infections. In order to overcome MRSA infection, we synthesized compound A, a lincomycin derivative, and evaluated the biological properties. The MIC₅₀ and MIC₉₀ values of compound A against MRSA clinical isolates, which were susceptible to clindamycin, from infected skin in Japan were 0.12 and 0.25 μg ml^-1, respectively, and those against hospital-acquired MRSA with clindamycin resistance were 1.0 and 2.0 μg ml^-1, respectively. Linezolid non-susceptible MRSA selected in the laboratory had mutations in the 23S rRNA gene and exhibited cross-resistance to compound A. MRSA non-susceptible to compound A selected in laboratory was not cross-resistant to linezolid, implying that the binding site to 23S rRNA partly overlaps with clindamycin and linezolid. The in vivo efficacies of compound A against mouse skin abscess model infected with clindamycin-susceptible and -resistant MRSA were superior to those of clindamycin and linezolid, respectively. The well-known linezolid-induced myelosuppression is caused by its inhibitory effect on mitochondrial function, but inhibition was weaker for compound A than that of linezolid. In short, compound A has broader anti-MRSA activities than clindamycin and linezolid due to additional binding site, and demonstrated preferable safety profile as a potential anti-MRSA drug.