Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

Cox, Georgina; Ejim, Linda; Stogios, Peter J.; Koteva, Kalinka; Bordeleau, Emily; Evdokimova, Elena; Sieron, Arthur O.; Savchenko, Alexei; Serio, Alisa W.; Krause, Kevin M.; Wright, Gerard D.

doi:10.1021/acsinfecdis.8b00001

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

Journal Article · Tue Apr 10 00:00:00 EDT 2018 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.8b00001· OSTI ID:1459983

Cox, Georgina ^[1]; Ejim, Linda ^[1]; Stogios, Peter J. ^[2]; Koteva, Kalinka ^[1]; Bordeleau, Emily ^[1]; Evdokimova, Elena ^[2]; Sieron, Arthur O. ^[1]; ^[3]; Serio, Alisa W. ^[4]; Krause, Kevin M. ^[4]; ^[1]

McMaster Univ., Hamilton, ON (Canada)
Univ. of Toronto, ON (Canada)
Univ. of Toronto, ON (Canada); Univ. of Calgary, AB (Canada)
Achaogen, San Francisco, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (US). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1459983

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 6 Vol. 4; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Discovery of a novel integron-borne aminoglycoside resistance gene present in clinical pathogens by screening environmental bacterial communities Böhm, Maria-Elisabeth; Razavi, Mohammad; Marathe, Nachiket P. Microbiome, Vol. 8, Issue 1 https://doi.org/10.1186/s40168-020-00814-z	journal	March 2020
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In Vitro Activity of Plazomicin against Gram-Negative and Gram-Positive Isolates Collected from U.S. Hospitals and Comparative Activities of Aminoglycosides against Carbapenem-Resistant Enterobacteriaceae and Isolates Carrying Carbapenemase Genes Castanheira, Mariana; Davis, Andrew P.; Mendes, Rodrigo E. Antimicrobial Agents and Chemotherapy, Vol. 62, Issue 8 https://doi.org/10.1128/aac.00313-18	journal	June 2018
In Vitro Activity of Plazomicin Compared to Amikacin, Gentamicin, and Tobramycin against Multidrug-Resistant Aerobic Gram-Negative Bacilli Fleischmann, Wim A.; Greenwood-Quaintance, Kerryl E.; Patel, Robin Antimicrobial Agents and Chemotherapy, Vol. 64, Issue 2 https://doi.org/10.1128/aac.01711-19	journal	November 2019
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60 APPLIED LIFE SCIENCES
Antimicrobial agents
Carbohydrates
Crystal structure
Enterobacteriaceae
Modification
Peptides and proteins
aminoglycoside-modifying enzymes
antibiotic resistance
plazomicin

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

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References (32)

Cited By (11)

Figures / Tables (6)

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