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Aminoglycoside conformation and ring substituents dictate evasion from bacterial resistance mechanisms
Author(s) -
Dey Debayan,
Hoffer Eric D.,
Francis Dillion,
Dunham Christine M.,
Conn Graeme L.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04834
Subject(s) - ribosomal rna , aminoglycoside , ring (chemistry) , chemistry , stereochemistry , methylation , antibiotics , biochemistry , dna , gene , organic chemistry
Ribosomal RNA (rRNA) methylation by aminoglycoside‐resistance methyltransferases is presumed to reduce antibiotic activity by sterically occluding part of the drug binding site in helix 44 of 16S rRNA. However, for 4,6‐disubstituted deoxystreptamine (4,6‐DOS) aminoglycosides, the m 1 A1408 aminoglycoside resistance modification results in a wide range of bacterial resistance phenotypes with structurally similar drugs, from complete resistance to highly susceptible. Thus, for currently undefined reasons, some 4,6‐DOS aminoglycosides appear to be able to “evade” the effects of rRNA methylation at A1408. In contrast for the m 7 G1405 aminoglycoside resistance modification, all 4,6‐DOS aminoglycosides are rendered inactive. Why these same drugs are unable to evade this methylation is also currently not mechanistically understood. We will describe the development of a framework for understanding methylated rRNA‐antibiotic interactions through the evaluation of energetics of drug‐methylated rRNA complexes for a collection of 4,6‐DOS aminoglycosides. With computational calculations using Monte Carlo simulations and free energy maps of aminoglycosides, we probed the flexibility around each ring’s dihedral angles (ϕ/ψ) in rRNA bound poses and the contributions of Ring I substituents to drug binding. These analyses revealed three key molecular features that may contribute to evasion of m 1 A1408 modification: 1) The polarity of atoms of the Ring I 6’ substituent; 2) the number of Ring I substituents; and 3) the presence of a L‐hydroxyaminobuteroyl amide (HABA) group on the 2‐DOS core ring. These studies lay a foundation for understanding aminoglycoside‐methylated rRNA interactions at the molecular level and could, for example, directly facilitate design of new aminoglycoside derivatives that retain activity against pathogens harboring aminoglycoside‐resistance rRNA methyltransferases. Support or Funding Information This work was supported by National Institutes of Health grants R01‐AI088025 (to GLC) and Cystic Fibrosis Foundation postdoctoral fellowship DEY18F0 (to DD).