title: Derivatives of 4-dihydro-4-deoxy-4(R)-amino spectinomycin and their activity against susceptible and resistant Escherichia coli strains.
abstract: A number of alkyl and acyl derivatives of 4-dihydro-4-deoxy-4(R)-amino spectinomycin were tested against various Escherichia coli strains, possessing different susceptibilities to spectinomycin. The influence of the lipophilicity and the length of the side chain substituents of the derivatives was compared to both minimal inhibitory concentration values and stability to adenyltransferase. Derivatives with a chain length of more than 10 carbon atoms demonstrated a significantly higher activity against all investigated strains, whether susceptible or resistant. The same inhibitory effect was achieved with short-chain aminoacyl derivatives only against susceptible strains. Other short-chain derivatives possessed no advantage to spectinomycin. A 10-fold decrease in the affinity for adenyltransferase was achieved in compounds with a high lipophilicity (log P), i.e., in aliphatic substituted derivatives with a log P greater than 4 and in benzoyl-substituted derivatives with a log P greater than 2. Derivatives with branched alkyl chains and long side chains displayed a different mode of action than spectinomycin. They possessed strong activity against strains with an altered ribosomal binding site and a decreased influence of pH on antimicrobial activity.
mesh_terms: D004926:Escherichia coli / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D009713:Nucleotidyltransferases / Q000032:analysis; D000198:Spectinomycin / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000198:Spectinomycin; D009713:Nucleotidyltransferases; C020658:glutamine-synthetase adenylyltransferase