Encoding of Promiscuity in an Aminoglycoside Acetyltransferase

Aminoglycoside antibiotics are a
large family of antibiotics that
can be divided into two distinct classes on the basis of the substitution
pattern of the central deoxystreptamine ring. Although aminoglycosides
are chemically, structurally, and topologically diverse, some aminoglycoside-modifying
enzymes (AGMEs) are able to inactivate as many as 15 aminoglycosides
from the two main classes, the kanamycin- and neomycin-based antibiotics.
Here, we present the crystal structure of a promiscuous AGME, aminoglycoside-N3-acetyltransferase-IIIb (AAC-IIIb), in the apo form, in
binary drug (sisomicin, neomycin, and paromomycin) and coenzyme A
(CoASH) complexes, and in the ternary neomycin–CoASH complex.
These data provide a structural framework for interpretation of the
thermodynamics of enzyme–ligand interactions and the role of
solvent in the recognition of ligands. In combination with the recent
structure of an AGME that does not have broad substrate specificity,
these structures allow for the direct determination of how antibiotic
promiscuity is encoded in some AGMEs.