Structural Analysis of the Tobramycin and Gentamicin Clinical Resistome Reveals Limitations for Next-generation Aminoglycoside Design.

Abstract:

:Widespread use and misuse of antibiotics has allowed for the selection of resistant bacteria capable of avoiding the effects of antibiotics. The primary mechanism for resistance to aminoglycosides, a broad-spectrum class of antibiotics, is through covalent enzymatic modification of the drug, waning their bactericidal effect. Tobramycin and gentamicin are two medically important aminoglycosides targeted by several different resistance factors, including aminoglycoside 2″-nucleotidyltransferase [ANT(2″)], the primary cause of aminoglycoside resistance in North America. We describe here two crystal structures of ANT(2″), each in complex with AMPCPP, Mn(2+), and either tobramycin or gentamicin. Together these structures outline ANT(2″)'s specificity for clinically used substrates. Importantly, these structures complete our structural knowledge for the set of enzymes that most frequently confer clinically observed resistance to tobramycin and gentamicin. Comparison of tobramycin and gentamicin binding to enzymes in this resistome, as well as to the intended target, the bacterial ribosome, reveals surprising diversity in observed drug-target interactions. Analysis of the diverse binding modes informs that there are limited opportunities for developing aminoglycoside analogs capable of evading resistance.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Bassenden AV,Rodionov D,Shi K,Berghuis AM

doi

10.1021/acschembio.5b01070

subject

Has Abstract

pub_date

2016-05-20 00:00:00

pages

1339-46

issue

5

eissn

1554-8929

issn

1554-8937

journal_volume

11

pub_type

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