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PubMed2026

Fatty Acid Biosynthesis Inhibitors─Fabimycin and Triclosan─Trigger Distinct Resistance Mutations in FabI and Potently Kill Gram-Negative Pathogens.

In an effort to develop efficacious antibacterials that engage targets for which there is no preexisting resistance, inhibition of the enoyl-acyl carrier protein reductase FabI has shown promise, with triclosan and fabimycin as representative members of the two major drug classes that show activity against important bacterial pathogens. Here, we use a morbidostat and whole-genome sequencing approach to comprehensively evaluate the resistance profiles that arise in pathogenic bacteria in response to these FabI inhibitors. When assessed against E. coli, fabimycin and triclosan were found to induce primarily nonoverlapping resistance profiles, leading to minimal cross-resistance between the two compounds. Furthermore, in vivo evaluation of the prominent resistant mutants indicates poor fitness, with the fittest mutant still susceptible to fabimycin. Collectively, these results suggest the combination use of two antibiotics that engage different positions on the same target as a means to kill pathogenic bacteria and limit resistance.

Triclosan↗
PubMed1975

Multiple forms of beta-ketoacyl-acyl carrier protein synthetase in Escherichia coli.

Two forms of beta-ketoacyl-acyl carrier protein (ACP) synthetase (designated I and II) have been identified in extracts of Escherichia coli. Synthetase I corresponds to the condensing enzyme that was studied earlier (GREENSPAN, M.D., ALBERTS, A.W., and VAGELOS, P.R. (1969) J. Biol. Chem. 244, 6477-6485); synthetase II represents a new form of the enzyme. Synthetase II was isolated as a homogeneous protein. It differs from synthetase I in having a higher molecular weight (76,999 versus 66,000), a lower pH optimum (5.5 to 6.1 versus 7.2), and a greater resistance to denaturation by heat. Synthetase II is similar to synthetase I in that both are inactivated by iodoacetamide, and prior incubation of the enzymes with fatty acyl thioesters prevents the inhibitory effect of iodoacetamide. Both also react with a fatty acyl thioester to form an acyl-enzyme intermediate, and the latter reacts with malonyl-ACP to form a beta-ketoacyl thioester. Specificity studies indicated that synthetase II, like synthetase I, has similar affinities with saturated and cis unsaturated fatty acyl thioesters of ACP that are intermediates in the synthesis of saturated and unsaturated fatty acids, respectively. The two synthetases differ only with respect to reactivity with palmitoleyl thioesters: synthetase II has a lower Km and higher Vmax than synthetase I with palmitoleyl-ACP. This finding suggests that synthetase II functions specifically in the elongation of palmitoleyl-ACP to form cis-vaccenyl-ACP. An investigation of synthetases I and II in two classes of unsaturated fatty acid auxotrophs revealed that synthetase I is absent in one class, fabB. Addition of wild type synthetase I to fabB fatty acid synthetase, which synthesizes only saturated fatty acids, permitted this fatty acid synthetase to synthesize unsaturated fatty acids. These experiments indicate that synthetase I plays a critical role in the synthesis of unsaturated fatty acids.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗
PubMed1976

Selection and properties of Escherichia coli mutants defective in the synthesis of cyclopropane fatty acids.

Mutants of Escherichia coli K-12 defective in the synthesis of cyclopropane fatty acids (CFA) have been selected and isolated by a L-[methyl-3H]methionine suicide procedure. Two mutants were isolated. Stationary-phase cultures of both mutants contain less than 0.7% of the CFA content found in the parental strain. The CFA deficiency is attributed to a deficiency of CFA synthetase activity. Extracts of both mutants contain less than 10% of the CFA synthetase activity found in extracts of the parental strain. Experiments in which parental and mutant extracts were mixed indicate that the lack of activity in the mutant strains is not due to an inhibitor of CFA synthetase present in the mutant extracts. We have not yet detected a physiological phenotype for these mutants. These strains grow normally at various temperatures in a variety of media. We have tested survival (colony-forming ability) in response to (i) prolonged incubation in stationary phase, (ii) exposure to drying, and (iii) exposure to detergents, heavy metals, low pH, high salt concentration, and a variety of other environmental conditions. The survival of both mutants is identical to that of the parental strain under all conditions tested. The compositions (excepting the CFA deficiency) and metabolic turnover rates of the phospholipids of both mutant strains are indistinguishable from those of the wild-type strain. The transport of several amino acids also seems normal in these mutants.

Cell-Free System↗
PubMed1975

Temperature-sensitive mutants of the yeast fatty-acid-synthetase complex.

By genetic complementation analysis, 88 independently isolated temperature-sensitive fatty acid synthetase mutants have been assigned to the six different fas-complementation groups II (fas 1), III (fas 1), Vb (fas 1), VI (fas 2), VIII (fas 2) and IX (fas 2). The complementation groups Va, Vc, Vd, IV and VII observed among nonconditional fas-mutants have not been found among the temperature-sensitive strains studied. From the failure to detect pantetheine-deficient conditional fas-mutants it is concluded that the yease acyl-carrier protein has an exceptionally stable tertiary structure. Furthermore, the lack of temperature-sensitive mutants of complementation group IV possibly indicates that this group specifically represents only nonsense and frameshift mutations. Almost half of the temperature-sensitive fas 1 and fas 2 mutants studied exhigited non-complementing characteristics. These results confirm the existence of non-complementing fas1 and fas2 missense mutations. From this it is concluded that both fatty acid synthetase loci encode multifunctional polypeptide chains rather than several monofunctional component enzymes. The possible existence of an independent acyl-carrier protein, as suggested by the genetic data reported in this study, is discussed. With 10 different temperature-sensitive fas1 and fas2 mutants the dependence of cellular growth rates on growth temperature and fatty acid supplementation was determined. With all mutants studied fatty-acid-independent growth was completely suppressed at non-permissive temperatures (34 -37 degrees C). In fatty-acid-supplemented media, however, these mutants exhibited the same growth characteristics as wild-type yeast cells. In contrast to this, wild-type yeast growth was found to be fatty-acid-independent at all temperatures studied. Other than in vivo, the purified fatty acid synthetase isolated from five different temperature-sensitive fas1 and fas2 mutants exhibited in vitro no increased thermolability compared to the wild-type enzyme. From this it is concluded that the specific conformation of fatty acid synthetase subunits either forms only at the ribosomal level during translation, or that this conformation is stabilized by the assembly of subunits into the multienzyme complex structure.

Binding Sites↗