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Journal of Bacteriology, May 2001, p. 3032-3040, Vol. 183, No. 10
0021-9193/01/$04.00+0   DOI: 10.1128/JB.183.10.3032-3040.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Response of Bacillus subtilis to Cerulenin and Acquisition of Resistance

Gustavo E. Schujman,1 Keum-Hwa Choi,2 Silvia Altabe,1 Charles O. Rock,2,3,* and Diego de Mendoza1

Instituto de Biología Molecular y Celular de Rosario (IBR) and Departamento de Microbiologia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000-Rosario, Argentina1; Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 381052; and Department of Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 381633

Received 23 October 2000/Accepted 22 February 2001

Cerulenin is a fungal mycotoxin that potently inhibits fatty acid synthesis by covalent modification of the active site thiol of the chain-elongation subtypes of beta -ketoacyl-acyl carrier protein (ACP) synthases. The Bacillus subtilis fabF (yjaY) gene (fabFb) encodes an enzyme that catalyzes the condensation of malonyl-ACP with acyl-ACP to extend the growing acyl chain by two carbons. There were two mechanisms by which B. subtilis adapted to exposure to this antibiotic. First, reporter gene analysis demonstrated that transcription of the operon containing the fabF gene increased eightfold in response to a cerulenin challenge. This response was selective for the inhibition of fatty acid synthesis, since triclosan, an inhibitor of enoyl-ACP reductase, triggered an increase in fabF reporter gene expression while nalidixic acid did not. Second, spontaneous mutants arose that exhibited a 10-fold increase in the MIC of cerulenin. The mutation mapped at the B. subtilis fabF locus, and sequence analysis of the mutant fabF allele showed that a single base change resulted in the synthesis of FabFb[I108F]. The purified FabFb and FabFb[I108F] proteins had similar specific activities with myristoyl-ACP as the substrate. FabFb exhibited a 50% inhibitory concentration (IC50) of cerulenin of 0.1 µM, whereas the IC50 for FabFb[I108] was 50-fold higher (5 µM). These biochemical data explain the absence of an overt growth defect coupled with the cerulenin resistance phenotype of the mutant strain.

* Corresponding author. Mailing address: Biochemistry Department, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-3491. Fax: (901) 525-8025. E-mail: charles.rock{at}stjude.org or diegonet{at}citynet.net.ar.

Journal of Bacteriology, May 2001, p. 3032-3040, Vol. 183, No. 10
0021-9193/01/$04.00+0   DOI: 10.1128/JB.183.10.3032-3040.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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