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

Autor: Yoko Hirai, Ko Kumura, Keiko Yamada, Kazunori Maebashi, Yoshinari Wakiyama, Eijiro Umemura, Keiichi Ajito
Rok vydání: 2020
Předmět:
0301 basic medicine
Drug
Male
Methicillin-Resistant Staphylococcus aureus
media_common.quotation_subject
030106 microbiology
Mitochondria
Liver
Microbial Sensitivity Tests
medicine.disease_cause
01 natural sciences
Microbiology
03 medical and health sciences
chemistry.chemical_compound
Mice
In vivo
23S ribosomal RNA
Drug Discovery
Drug Resistance
Bacterial
medicine
Animals
media_common
Pharmacology
Mice
Inbred ICR
Binding Sites
biology
010405 organic chemistry
Chemistry
Clindamycin
Linezolid
biochemical phenomena
metabolism
and nutrition
Staphylococcal Infections
bacterial infections and mycoses
biology.organism_classification
Methicillin-resistant Staphylococcus aureus
Abscess
0104 chemical sciences
Anti-Bacterial Agents
Lincomycin
RNA
Ribosomal
23S
Staphylococcus aureus
Female
Bacteria
medicine.drug
Zdroj: The Journal of antibiotics. 74(2)
ISSN: 1881-1469
Popis: 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.
Databáze: OpenAIRE
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