Structure-based design, synthesis, and A-site rRNA cocrystal complexes of functionally novel aminoglycoside antibiotics: C2" ether analogues of paromomycin.
A series of 2"-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit microM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, P. Q., Canada. stephen.hanessian@umontreal.ca
Szychowski
Janek
J
Adhikari
Susanta Sekhar
SS
Vasquez
Guillermo
G
Kandasamy
Pachamuthu
P
Swayze
Eric E
EE
Migawa
Michael T
MT
Ranken
Ray
R
François
Boris
B
Wirmer-Bartoschek
Julia
J
Kondo
Jiro
J
Westhof
Eric
E
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010303:Paromomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012335:RNA, Ribosomal / Q000737:chemistry*; D018805:Sepsis / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004987:Ethers; D012335:RNA, Ribosomal; D010303:Paromomycin