Escherichia coli susceptible to glycopeptide antibiotics.
Mutants of Escherichia coli susceptible to vancomycin were isolated after mutagenesis with nitrosoguanidine. One such mutant was studied extensively. Multiple regression analysis of the relationship between physical properties of 20 glycopeptides and their in vitro activities against the vancomycin-susceptible mutant revealed a significant correlation with molecular mass (P = 0.007). pI, hydrophobicity, and affinity of the glycopeptide for the pentapeptide target were not as important for activity. This suggested that a block of access of the antibiotic to its target could be the major factor determining activity. Outer membrane proteins of the vancomycin-susceptible mutant, resistant parent, and revertant strains appeared normal. The mutant exhibited increased susceptibility to both erythromycin and fusidic acid which was lost in single-step revertants to vancomycin resistance. Polymyxin B nonapeptide was synergistic with erythromycin and fusidic acid against the parent and revertant but not against the susceptible mutant. Analysis of the susceptibilities of control strains of E. coli and Salmonella typhimurium with known defects in lipopolysaccharide (LPS) synthesis revealed that core LPS mutants (Re chemotype) were phenotypically similar to the E. coli mutant under study. However, the LPS core of the mutant migrated slightly less rapidly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis than wild-type or revertant core LPS and did not resemble Re chemotype LPS core obtained from Salmonella rfaC and rfaD mutants. These data suggest that defects in LPS core structure other than loss of heptose moieties may also be important in loss of resistance to large, hydrophilic molecules such as glycopeptides.
Shlaes
D M
DM
Département de Microbiologie Médicale, Faculté de Médecine, Université Pierre et Marie Curie, Paris, France.
Shlaes
J H
JH
Davies
J
J
Williamson
R
R
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002846:Chromatography, Affinity; D004352:Drug Resistance, Microbial; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D006020:Glycopeptides / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000032:analysis; D009153:Mutagens; D009604:Nitrosoguanidines / Q000494:pharmacology; D010457:Peptidoglycan / Q000096:biosynthesis; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D008070:Lipopolysaccharides; D009153:Mutagens; D009604:Nitrosoguanidines; D010457:Peptidoglycan