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.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Agostino JW, Ferguson JK, Eastwood K, Kirk MD. The increasing importance of community-acquired methicillin-resistant Staphylococcus aureus infections. Med J Aust. 2017;207:388–93.
Coombs GW, et al. Community-onset Staphylococcus aureus Surveillance Programme annual report, 2012. Commun Dis Intell Q Rep. 2014;38:E59–69.
Peterson AE. et al. Molecular and phenotypic characteristics of healthcare- and community-associated methicillin-resistant Staphylococcus aureus at a rural hospital. PLoS ONE. 2012;7:e38354.
Flanagan S, et al. Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function. Antimicrob Agents Chemother. 2015;59:178–85.
Iguchi S, Mizutani T, Hiramatsu K, Kikuchi K. Rapid acquisition of linezolid resistance in methicillin-resistant Staphylococcus aureus: role of hypermutation and homologous recombination. PLoS ONE. 2016;11:e0155512.
Wakiyama Y, et al. Synthesis and SARs of novel lincomycin derivatives Part 5: optimization of lincomycin analogs exhibiting potent antibacterial activities by chemical modification at the 6- and 7-positions. J Antibiot. 2018;71:298–317.
Rogers DE, Melly MA. Further observations on the behavior of staphylococci within human leukocytes. J Exp Med. 1960;111:533–58.
Tadashi B, et al. Genome and virulence determinants of high virulence community-acquired MRSA. Lancet. 2002;359:1819–27.
Soni I, Chakrapani H, Chopra S. Draft genome sequence of methicillin-sensitive Staphylococcus aureus ATCC 29213. Genome Announc. 2015;3:e01095–15.
Kuroda M, et al. Whole genome sequencing of meticillin-resistant Staphylococcus aureus. Lancet. 2001;357:1225–40.
Weinstein MP, et al. Performance standards for antimicrobial susceptibility testing. 30th ed. CLSI Supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2020.
Douthwaite S. Interaction of the antibiotics clindamycin and lincomycin with Escherichia coli 23S ribosomal RNA. Nucleic Acids Res. 1992;20:4717–20.
David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev. 2010;23:616–87.
Braun L, Craft D, Williams R, Tuamokumo F, Ottolini M. Increasing clindamycin resistance among methicillin-resistant Staphylococcus aureus in 57 northeast United States military treatment facilities. Pediatr Infect Dis J. 2005;24:622–6.
Wakiyama Y, et al. Synthesis and structure–activity relationships of novel lincomycin derivatives. Part 2. Synthesis of 7(S)-7-deoxy-7-(4-morpholino carbonylphenylthio)lincomycin and its 3-dimensional analysis with rRNA. J Antibiot. 2016;69:428–39.
Davidovich C, Bashan A, Yonath A. Structural basis for cross-resistance to ribosomal PTC antibiotics. PNAS. 2008;105:20665–70.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Hirai, Y., Maebashi, K., Yamada, K. et al. Characterization of compound A, a novel lincomycin derivative active against methicillin-resistant Staphylococcus aureus. J Antibiot 74, 124–132 (2021). https://doi.org/10.1038/s41429-020-00375-1