title: Studies on the mechanism of inhibition of bacterial ribonuclease P by aminoglycoside derivatives.
abstract: Ribonuclease P (RNase P) is a Mg2+-dependent endoribonuclease responsible for the 5'-maturation of transfer RNAs. It is a ribonucleoprotein complex containing an essential RNA and a varying number of protein subunits depending on the source: at least one, four and nine in Bacteria, Archaea and Eukarya, respectively. Since bacterial RNase P is required for viability and differs in structure/subunit composition from its eukaryal counterpart, it is a potential antibacterial target. To elucidate the basis for our previous finding that the hexa-arginine derivative of neomycin B is 500-fold more potent than neomycin B in inhibiting bacterial RNase P, we synthesized hexa-guanidinium and -lysyl conjugates of neomycin B and compared their inhibitory potential. Our studies indicate that side-chain length, flexibility and composition cumulatively account for the inhibitory potency of the aminoglycoside-arginine conjugates (AACs). We also demonstrate that AACs interfere with RNase P function by displacing Mg2+ ions. Moreover, our finding that an AAC can discriminate between a bacterial and archaeal (an experimental surrogate for eukaryal) RNase P holoenzyme lends promise to the design of aminoglycoside conjugates as selective inhibitors of bacterial RNase P, especially once the structural differences in RNase P from the three domains of life have been established.
authors: Department of Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
authors: Steven A
authors: SA
authors: Kawamoto
authors: Christopher G
authors: CG
authors: Sudhahar
authors: Cynthia L
authors: CL
authors: Hatfield
authors: Jing
authors: J
authors: Sun
authors: Edward J
authors: EJ
authors: Behrman
authors: Venkat
authors: V
authors: Gopalan
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001105:Archaea / Q000201:enzymology; D001120:Arginine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005601:Framycetin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008274:Magnesium / Q000737:chemistry; D008969:Molecular Sequence Data; D043262:Ribonuclease P / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D006146:Guanidines; C527286:NeoG6 compound; C527287:NeoK6 compound; C527288:NeoR5 compound; D005601:Framycetin; D001120:Arginine; D043262:Ribonuclease P; C470865:ribonuclease P, E coli; D008274:Magnesium; D008239:Lysine