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Antimicrobial Agents and Chemotherapy, August 1998, p. 2041-2047, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Acquisition of Certain Streptomycin-Resistant (str) Mutations Enhances Antibiotic Production in Bacteriadagger

Yoshiko Hosoya,1 Susumu Okamoto,1 Hideyuki Muramatsu,2 and Kozo Ochi1,*

National Food Research Institute,1 and Exploratory Research Laboratories, Fujisawa Pharmaceutical Co.,2 Tsukuba, Ibaraki, Japan

Received 3 February 1998/Returned for modification 5 May 1998/Accepted 9 June 1998

Physiological differentiation (including antibiotic production) in microorganisms usually starts when cells encounter adverse environmental conditions and is frequently accompanied by an increase in the accumulation of intracellular ppGpp. We have found that the acquisition of certain streptomycin-resistant (str) mutations enables cells to overproduce antibiotics, demonstrating an increase in productivity 5- to 50-fold greater than that of wild-type strains. The frequency of such antibiotic-overproducing strains among the str mutants was shown to range from 3 to 46%, as examined with several strains of the genera Streptomyces, Bacillus, and Pseudomonas. Analysis of str mutants from Bacillus subtilis Marburg 168 revealed that a point mutation occurred within the rpsL gene, which encodes the ribosomal protein S12, changing Lys-56 (corresponding to Lys-43 in Escherichia coli) to Asn, Arg, Thr, or Gln. Antibiotic productivity increased in a hierarchical manner depending upon which amino acid residue replaced Lys at this position. The strA1 mutation, a genetic marker frequently used for mapping, had no effect on antibiotic productivity even though it was found to result in an amino acid alteration of Lys-56 to Ile. Gene replacement experiments with the str alleles demonstrated unambiguously that the str mutation is responsible for the antibiotic overproductivity observed. These results offer a rational approach for improving the production of antibiotic (secondary metabolism) from microorganisms.

* Corresponding author. Mailing address: National Food Research Institute, 2-1-2 Kannondai, Tsukuba, Ibaraki 305-8642, Japan. Phone: 81-298-38-8125. Fax: 81-298-38-7996. E-mail: kochi{at}ss.nfri.affrc.go.jp.

dagger Dedicated to the late Edward Katz for his pioneering work regarding the implication of antibiotics in microbial secondary metabolism.

Antimicrobial Agents and Chemotherapy, August 1998, p. 2041-2047, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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