Restoration of Drug-Resistant Bacteria to Sensitivity to Chemotherapeutic Drugs
WALTER REED ARMY INST OF RESEARCH WASHINGTON DC
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Bacterial diseases caused by drug-resistant organisms present major problems in military medicine. Clinical foremost quinacrine as well as experimental pharmaceuticals and dyes restored drug-resistant bacteria to sensitivity to chemotherapeutic drugs when this resistance was caused by episomal R-factors. This was first shown in model experiments with Escherichia coli and subsequently with pathogenic Klebsiella pneumoniae and, especially, with Salmonella typhimurium. Maximally, more than 95 per cent of cells of S. typhimurium regained sensitivity to the antibiotic drug, kanamycin, when grown in the presence of ethidium bromide. The mechanism underlying the elimination of resistance determinants is the formation of complexes of active with R-factor DNA followed by selective inhibition of its replication. The fate of the episomal Flac DNA upon elimination of the lac determinant with quinacrine was studied biophysically. Since R-factor DNA is closed circular in its molecular architecture, the eliminating compounds act not only by stabilizing double-helical DNA to strand separation but also wind up the DNA circles into artificial supercoils whose biochemical functionality is suspended.