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Antimicrob Agents Chemother. 1976 August; 10(2): 333-343
Copyright © 1976 American Society for Microbiology. All Rights Reserved.

Specific Action of 4-Nitropyridine 1-Oxide on Escherichia coli K-12 Pro⁺ Strains Leading to the Isolation of Proline-Requiring Mutants: Mechanism of Action of 4-Nitropyridine 1-Oxide

^a Department of Chemistry, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920, Japan

ABSTRACT

Possible mechanisms involved in the action of 4-nitropyridine 1-oxide (4NPO) on Escherichia coli K-12 pro⁺ cells in Penassay broth leading to the selective isolation of proA^– and/or proB^– mutants but not proC^– mutant were studied. Reconstruction experiments between pro⁺ and pro^– cells, together with experiments on the bactericidal action of 4NPO on pro⁺ and pro^– cells, indicated that 4NPO is more toxic for pro⁺ and proC^– cells than for proA^– and proB^– cells. These results, coupled with data indicating little mutagenicity of 4NPO on E. coli cells, led us to conclude that the selection of proA^– and/or proB^– cells that arose spontaneously in the pro⁺ culture is a possible mechanism for the action of 4NPO. Examination of 4NPO sensitivity of pro⁺ transductants derived from proA^– and proB^– cells with P1 vir phage and pro⁺ cells as donor and of pro⁺ spontaneous revertants derived from those pro^– cells suggested that 4NPO-sensitive gene(s) should be on, or very close to, the proA and proB loci and that both products of proA and proB genes may be involved in the sensitivity of bacteria to 4NPO. The fact that the 4NPO-sensitive allele is dominant over the 4NPO-resistant allele further indicated the possible correlation between gene products of proA and proB and the 4NPO sensitivity of bacteria. Experiments on metabolic conversion of 4NPO with bacterial cells proved that the major metabolic pathway of the agent is reduction to (possibly via 4-nitroso-) 4-hydroxylamino- and 4-amino-pyridine 1-oxides, and then to 4-aminopyridine. Investigation of the effect of structural modification of 4NPO on the elective selection of Pro^– mutants in Pro⁺ culture further suggested that the structural feature indispensable for the action of the agent is the hydroxyl-amino or its more oxidized state at the 4 position and the N-oxide moiety at the 1 position on the pyridine skeleton. Action of 4NPO in minimal medium was found to be bacteriostatic on pro⁺ cells but not on pro^– cells, leading to the formation of long nonseptate multinucleate filament cells on pro⁺ cells. Possible biochemical mechanisms of the selective toxicity of 4NPO for pro⁺ and pro^– cells are discussed.

¹ Present address: Department of Biology, University of California, San Diego, La Jolla, CA 92093.

² Present address: Research and Development Division, Eisai Co., 4 Koishikawa, Bunkyo 112, Tokyo, Japan.

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