The broad spectrum antibacterial properties of 2-hydroxydiphenyl ethers have been appreciated for decades, and their use in consumer products is rapidly increasing. We identify the enoyl-acyl carrier protein reductase (fabI) component of the type II fatty acid synthase system as the specific cellular target for these antibacterials. Biologically active 2-hydroxydiphenyl ethers effectively inhibit fatty acid synthesis in vivo and FabI activity in vitro. Resistant mechanisms include upregulation of fabI expression and spontaneously arising missense mutations in the fabI gene. These results contradict the view that these compounds directly disrupt membranes and suggest that their widespread use will select for resistant bacterial populations.The fabI gene of Escherichia coli encodes the NADH-dependent trans-2-enoyl-acyl carrier protein (ACP) 1 reductase of bacterial fatty acid synthesis (1). Bacteria utilize the type II, or dissociated, fatty acid biosynthetic system (2-4), which consists of a collection of distinct polypeptides that each carry out a unique reaction in the biosynthetic cycle. FabI catalyzes the last step in each cycle of elongation and is an important regulatory point in the pathway, playing a determinant role in completing each round of elongation (5, 6). The enoyl-ACP reductase of Mycobacterium tuberculosis, InhA, is the target for a metabolite of isoniazid, a compound used in the treatment of tuberculosis (7-9). E. coli FabI is inhibited by a class of heterocyclic, boron-containing compounds (diazaborines) (1). In both cases, the drugs bind together with NAD at the active site, and resistant enzymes arise from mutations that alter the residues that form the NADH binding pocket (10,11). The recent work identifying enoyl-ACP reductase as the target for these therapeutic agents has stimulated research into developing a second generation of antibacterial drugs that inhibit FabI and bacterial fatty acid synthesis.2-Hydroxydiphenyl ethers are a class of compounds that exhibit broad spectrum antimicrobial activity (Fig. 1). Many of these compounds were initially used in the treatment of textiles, and there have been hundreds of patents filed worldwide for their incorporation into a diverse range of products over the last 30 years. Triclosan (VI) is the most potent and widely used member of this class in contemporary consumer products as a microbicide. For example, triclosan is a component of deodorant soaps, dermatological and topical preparations for skin, oral rinses, toothpastes, and is even incorporated into the plastics of children's toys (12). Triclosan has long been thought to disrupt the cell membrane, rendering bacteria unable to assimilate nutrients and proliferate (13)(14)(15). This view of triclosan acting as a nonspecific biocide has provided the rationale for its use in consumer products and predicts that the emergence of resistant strains is very unlikely. While our work was in progress, a scientific correspondence reported that E. coli strains that were selected for resistance to triclo...

Escherichia coli grows on long-chain fatty acids after a distinct lag phase. Cells, preadapted to palmitate, grow immediately on fatty acids, indicating that fatty acid oxidation in this bacterium is an inducible system. This hypothesis is supported by the fact that cells grown on palmitate oxidize fatty acids at rates 7 times faster than cells grown on amino acids and 60 times faster than cells grown on a combined medium of glucose and amino acids. The inhibitory effect of glucose may be explained in terms of catabolite repression. The activities of the five key enzymes of

The re-emergence of tuberculosis infections which are resistant to conventional drug therapy has demonstrated the need for alternative chemotherapy against Mycobacterium tuberculosis. As part of a study to optimize the quinolone antibacterials against M. tuberculosis, we have prepared a series of N-1- and C-7-substituted quinolones to examine specific structure-activity relationships between modifications of the quinolone at these two positions and activity against mycobacteria. The compounds, synthesized by literature procedures, were evaluated for activity against Mycobacterium fortuitum and Mycobacterium smegmatis as well as Gram-negative and Gram-positive bacteria. The activity of the compounds against M. fortuitum was used as a barometer of M. tuberculosis activity. The results demonstrate that (i) the activity against mycobacteria was related more to antibacterial activity than to changes in the lipophilicity of the compounds, (ii) the antimycobacterial activity imparted by the N-1 substituent was in the order tert-butyl > or = cyclopropyl > 2,4-difluorophenyl > ethyl approximately cyclobutyl > isopropyl, and (iii) substitution with either piperazine or pyrrolidine heterocycles at C-7 afforded similar activity against mycobacteria.