Mode of action of the cyclic depsipeptide antibiotic LL-AO341 beta 1 and partial characterization of a Staphylococcus aureus mutant resistant to the antibiotic.
The antibacterial activity of the cyclic antibiotic LL-AO341 beta 1 was examined. The antibiotic was a narrow spectrum agent, effective principally against Gram-positive organisms. The intrinsic insusceptibility of Escherichia coli was due to exclusion of the drug by the outer membrane. The antibiotic was bactericidal against Staphylococcus aureus, and cell death was associated with lysis of the bacteria. The antibiotic did not specifically inhibit the synthesis of DNA, RNA, protein, lipid or peptidoglycan since these synthetic activities continued for several minutes after exposure to lethal concentrations of the antibiotic and then all abruptly ceased between about 8 and 15 minutes post antibiotic exposure. These results are consistent with the cytoplasmic membrane being the primary target for LL-AO341 beta 1. Mutants of S. aureus 8325-4 selected on 10- or 20-times the MIC of LL-AO341 beta 1 occurred spontaneously with a frequency of about 3 x 10(-6). A mutant expressing a 160-fold increase in the MIC of LL-AO341 beta 1 was obtained by exposing cultures to progressively increasing concentrations of the antibiotic. This mutant displayed no cross-resistance to other agents apart from telomycin (a structural analogue of LL-AO341 beta 1), apparently did not modify or degrade LL-AO341 beta 1 and had only a slightly longer doubling time than the parent strain.
Oliva
B
B
Infectious Disease Research Section, American Cyanamid, Lederle Laboratories, Pearl River, New York 10965.
Maiese
W M
WM
Greenstein
M
M
Borders
D B
DB
Chopra
I
I
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis; D002462:Cell Membrane / Q000187:drug effects; D004269:DNA, Bacterial / Q000096:biosynthesis; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D008055:Lipids / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010455:Peptides; D010457:Peptidoglycan / Q000096:biosynthesis; D011112:Polymyxin B / Q000031:analogs & derivatives / Q000494:pharmacology; D012329:RNA, Bacterial / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000648:ultrastructure
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; C086613:LL AO341beta1; D008055:Lipids; D010455:Peptides; D010457:Peptidoglycan; D012329:RNA, Bacterial; C009392:telomycin; C038934:polymyxin B nonapeptide; D011112:Polymyxin B