Adaptive acquisition of novobiocin resistance in Pasteurella multocida strains of avian origin

Naturally occurring strains of Pasteurella multocida are atypically suscept ible to hydrophobic antibiotics such as novobiocin. despite their Gram-nega tive cell envelope ultrastructure. Four strains adaptively resistant to 100 0 mu g/ml of novobiocin were obtained by sequentially subculturing cell sur face hydrophobic variants of avian origin in the presence of increasing ant ibiotic concentrations. Adaptive novobiocin resistance was accompanied in a ll cases by the concomitant acquisition of resistance to coumermycin, a hyd rophobic antibiotic possessing the same mechanism of action, but nor to the functionally disparate hydrophobic antibiotic rifamycin. The acquisition o f resistance was nor accompanied by alterations in the lipid composition of the cell envelope. Subsequent growth of adaptively resistant strains in th e absence of novobiocin did not result in the restoration of susceptibility to either novobiocin or coumermycin. Acquisition of adaptive resistance in encapsulated parental strains resulted in an inability to synthesize capsu lar material and enhanced cell surface hydrophobicity; however, parental en capsulation and decreased cell surface hydrophobicity were restored upon re moval of novobiocin. These data suggest that acquisition of adaptive resist ance to novobiocin conferred in this manner is the result of a stable genet ic event affecting the mechanistic target oi both novobiocin and coumermyci n rather than a physiological adaptation involving outer membrane impermeab ility.