Elucidation of resistance mechanism of fosfomycin in carbapenemase-producing Enterobacteriaceae

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17941
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Fujita Health University
• Principal Investigator: Ito Ryota 藤田医科大学, 医学部, 講師 (50813359)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 耐性菌 / ホスホマイシン / カルバペネム耐性腸内細菌目細菌

Outline of Final Research Achievements

We analyzed the mechanism of fosfomycin resistance in 77 strains of carbapenemase producing Enterobacteriaceae (48 Enterobacter cloacae complex strains and 29 Klebsiella pnuemoniae strains). Whole-genome sequencing and real-time PCR were performed, and all fosfomycin-resistant strains possessed the fosA gene, and it was clarified that the enzyme FosA greatly contributes to fosfomycin resistance from the protein expression level.
In addition, it was clarified that there are strains that develop fosfomycin resistance due to antimicrobial exposure, and that the cause is associated with the functional decline of the transporter system utilized by fosfomycin for cell entry.

Free Research Field

感染症

Academic Significance and Societal Importance of the Research Achievements

カルバペネマーゼ産生腸内細菌目細菌（Carbapenemase-producing Enterobacteriaceae，CPE）などの耐性菌の広がりが世界的に問題となっている。ホスホマイシンは1969年に発見された古くから使用されている抗菌薬である。過去に我々は、ホスホマイシンの耐性に関わるfosA遺伝子を阻害することで、これらの耐性菌にもホスホマイシンが有効となる可能性を示した。本研究で主要な耐性菌におけるホスホマイシン耐性機序が明らかとなり、今後fosA阻害剤の開発などの新薬創薬へつながることが期待される。