PMID:1729241
| Citation |
Tsay, JT, Rock, CO and Jackowski, S (1992) Overproduction of beta-ketoacyl-acyl carrier protein synthase I imparts thiolactomycin resistance to Escherichia coli K-12. J. Bacteriol. 174:508-13 |
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| Abstract |
Thiolactomycin [(4S)(2E,5E)-2,4,6-trimethyl-3-hydroxy-2,5,7-octatriene- 4-thiolide] (TLM) is a unique antibiotic structure that inhibits dissociated type II fatty acid synthase systems but not the multifunctional type I fatty acid synthases found in mammals. We screened an Escherichia coli genomic library for recombinant plasmids that impart TLM resistance to a TLM-sensitive strain of E. coli K-12. Nine independent plasmids were isolated, and all possessed a functional beta-ketoacyl-acyl carrier protein synthase I gene (fabB) based on their restriction enzyme maps and complementation of the temperature-sensitive growth of a fabB15(Ts) mutant. A plasmid (pJTB3) was constructed that contained only the fabB open reading frame. This plasmid conferred TLM resistance, complemented the fabB(Ts) mutation, and directed the overproduction of synthase I activity. TLM selectively inhibited unsaturated fatty acid synthesis in vivo; however, synthase I was not the only TLM target, since supplementation with oleate to circumvent the cellular requirement for an active synthase I did not confer TLM resistance. Overproduction of the FabB protein resulted in TLM-resistant fatty acid biosynthesis in vivo and in vitro. These data show that beta-ketoacyl-acyl carrier protein synthase I is a major target for TLM and that increased expression of this condensing enzyme is one mechanism for acquiring TLM resistance. However, extracts from a TLM-resistant mutant (strain CDM5) contained normal levels of TLM-sensitive synthase I activity, illustrating that there are other mechanisms of TLM resistance. |
| Links | |
| Keywords |
Acyltransferases/biosynthesis; Acyltransferases/chemistry; Acyltransferases/genetics; Carrier Proteins/biosynthesis; Carrier Proteins/chemistry; Carrier Proteins/genetics; Drug Resistance, Microbial/genetics; Escherichia coli/drug effects; Escherichia coli/enzymology; Escherichia coli/genetics; Fatty Acid Synthetase Complex/antagonists & inhibitors; Fatty Acids, Unsaturated/biosynthesis; Thiophenes/pharmacology |
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