Resistance to antibiotic synergism in Streptococcus faecalis: further studies with amikacin and with a new amikacin derivative, 4'-deoxy, 6'-N-methylamikacin.
Streptococcus faecalis strains may resist penicillin-aminoglycoside synergy by the production of plasmid-mediated aminoglycoside-modifying enzymes. One of these enzymes, aminoglycoside 3'-phosphotransferase, has been shown to have a broad range of substrate specificity, including amikacin. We have studied a derivative of amikacin, 4'-deoxy, 6'-N-methylamikacin (BB-K311), against 11 clinical blood isolates of S. faecalis. Minimal inhibitory concentrations of BB-K311 were quite similar to those of amikacin, ranging from 125 to 1,000 micrograms/ml. In assays for antibiotic synergy, penicillin and amikacin produced enhanced killing compared with the penicillin alone only against those three strains which lacked the phosphotransferase enzyme. The other eight enzyme-positive strains actually demonstrated significant antagonism between penicillin against all 11 strains, regardless of enzyme production. Analysis of substrate profiles with crude preparations of the aminoglycoside 3'-phosphotransferase enzyme confirmed that BB-K311 was a very poor substrate for modification, as expected from the synergy studies. Use of other aminoglycoside analogs confirmed the 3'-OH site of modification. These findings suggest that removing the 4'-OH group in amikacin effectively blocks 3'-phosphorylation by S. faecalis enzyme.
D000583:Amikacin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000201:enzymology; D007612:Kanamycin / Q000031:analogs & derivatives*; D019868:Kanamycin Kinase; D008826:Microbial Sensitivity Tests; D010770:Phosphotransferases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D007612:Kanamycin; C030518:4'-deoxy-6'-N-methylamikacin; D000583:Amikacin; D010770:Phosphotransferases; D019868:Kanamycin Kinase