Species-specific antibiotic-ribosome interactions: implications for drug development.
In the cell, the protein synthetic machinery is a highly complex apparatus that offers many potential sites for functional interference and therefore represents a major target for antibiotics. The recent plethora of crystal structures of ribosomal subunits in complex with various antibiotics has provided unparalleled insight into their mode of interaction and inhibition. However, differences in the conformation, orientation and position of some of these drugs bound to ribosomal subunits of Deinococcus radiodurans (D50S) compared to Haloarcula marismortui (H50S) have raised questions regarding the species specificity of binding. Revisiting the structural data for the bacterial D50S-antibiotic complexes reveals that the mode of binding of the macrolides, ketolides, streptogramins and lincosamides is generally similar to that observed in the archaeal H50S structures. However, small discrepancies are observed, predominantly resulting from species-specific differences in the ribosomal proteins and rRNA constituting the drug-binding sites. Understanding how these small alterations at the binding site influence interaction with the drug will be essential for rational design of more potent inhibitors.
Wilson
Daniel N
DN
Max-Planck-Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany.
Harms
Jörg M
JM
Nierhaus
Knud H
KH
Schlünzen
Frank
F
Fucini
Paola
P
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D034301:Deinococcus / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D019614:Haloarcula marismortui / Q000235:genetics / Q000378:metabolism; D048628:Ketolides / Q000378:metabolism; D055231:Lincosamides; D018942:Macrolides / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D012335:RNA, Ribosomal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D025361:Streptogramins / Q000378:metabolism
D000900:Anti-Bacterial Agents; D048628:Ketolides; D055231:Lincosamides; D018942:Macrolides; D012335:RNA, Ribosomal; D025361:Streptogramins