2. Academic Validation
  3. Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

  • ACS Infect Dis. 2018 Jun 8;4(6):980-987. doi: 10.1021/acsinfecdis.8b00001.
Georgina Cox 1,  Linda Ejim 1,  Peter J Stogios 2,  Kalinka Koteva 1,  Emily Bordeleau 1,  Elena Evdokimova 2,  Arthur O Sieron 1,  Alexei Savchenko 2 3,  Alisa W Serio 4,  Kevin M Krause 4,  Gerard D Wright 1
Affiliations

Affiliations

  • 1 M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, DeGroote School of Medicine , McMaster University , 1280 Main Street West , Hamilton , Ontario L8N 4K1 , Canada.
  • 2 Center for Structural Genomics of Infectious Diseases (CSGID) and Department of Chemical Engineering and Applied Chemistry , University of Toronto , Toronto , Ontario M5G 1L6 , Canada.
  • 3 Department of Microbiology, Immunology and Infectious Diseases, Health Research Innovation Centre , University of Calgary , 3330 Hospital Drive NW, HRIC-2C66 , Calgary , Alberta T2N 4N1 , Canada.
  • 4 Achaogen , One Tower Place, Suite 300 , South San Francisco , California 94080 , United States.
PMID: 29634241 DOI: 10.1021/acsinfecdis.8b00001
Abstract

Plazomicin is a next-generation, semisynthetic Aminoglycoside antibiotic currently under development for the treatment of infections due to multidrug-resistant Enterobacteriaceae. The compound was designed by chemical modification of the natural product sisomicin to provide protection from common Aminoglycoside modifying Enzymes that chemically alter these drugs via N-acetylation, O-adenylylation, or O-phosphorylation. In this study, plazomicin was profiled against a panel of isogenic strains of Escherichia coli individually expressing twenty-one Aminoglycoside resistance Enzymes. Plazomicin retained Antibacterial activity against 15 of the 17 modifying enzyme-expressing strains tested. Expression of only two of the modifying Enzymes, aac(2')-Ia and aph(2″)-IVa, decreased plazomicin potency. On the Other hand, expression of 16S rRNA ribosomal methyltransferases results in a complete lack of plazomicin potency. In vitro enzymatic assessment confirmed that AAC(2')-Ia and APH(2'')-IVa (Aminoglycoside acetyltransferase, AAC; Aminoglycoside phosphotransferase, APH) were able to utilize plazomicin as a substrate. AAC(2')-Ia and APH(2'')-IVa are limited in their distribution to Providencia stuartii and Enterococci, respectively. These data demonstrate that plazomicin is not modified by a broad spectrum of common Aminoglycoside modifying Enzymes including those commonly found in Enterobacteriaceae. However, plazomicin is inactive in the presence of 16S rRNA ribosomal methyltransferases, which should be monitored in future surveillance programs.

Keywords

Enterobacteriaceae; aminoglycoside-modifying enzymes; antibiotic resistance; plazomicin.

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