This review deals with the most recent findings on the antimalarial, antimycobacterial, and antifungal properties of fatty acids, with particular emphasis on novel marine fatty acids. The first section deals with the most recent and some background literature on what has been the latest developments with respect to fatty acids as antimalarial agents and the importance of enzyme inhibition, in particular the inhibition of the enoyl-ACP reductase (FabI) of Plasmodium falciparum, the principal agent responsible for malaria. This section of the review also emphasizes the latest antimalarial research with the very long-chain Delta5,9 fatty acids from sponges. The second section of the review deals with the recent literature on the antimycobacterial activity of fatty acids and the importance of enzyme inhibition, in particular the inhibition of the enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis for antimycobacterial activity. The inhibitory activities of the Delta5,9 fatty acids against InhA as well as that of the alpha-methoxylated fatty acids are also discussed. The importance of Delta5,9 fatty acids as topoisomerase I inhibitors and its connection to cancer is also reviewed. The last part of the review, the antifungal section, also emphasizes the most recent research with antifungal fatty acids and the importance of enzyme inhibition, in particular N-myristoyltransferase (NMT) inhibition, for antifungal activity. This last section of the review emphasizes the latest research with the alpha-methoxylated fatty acids but the importance of acetylenic fatty acids is also considered.

Here we report on the trophodynamics of the bacteria-containing coral reef sponge Halisarca caerulea. The assimilation and respiration of the 13 C-enriched substrates glucose, algal-derived dissolved and particulate organic matter (diatom-DOM and -POM), and bacteria were followed in 1-and 6-h incubations. Except for glucose, all substrates were readily processed by the sponge, with assimilation being the major fate. 13 C-Enrichment patterns in fatty acid biomarkers revealed that sponge dissolved organic 13 C assimilation was both direct and bacteria mediated as tracer carbon was recovered both in bacteria-specific and nonbacterial fatty acid. This is the first direct evidence of DOM incorporation by sponges. The present study demonstrates that the encrusting sponge H. caerulea feeds on both DOM and POM and given their dominant coverage of the largest coral reef habitat (coral cavities) it is proposed that organic matter assimilation by cryptic reef sponges may represent an important, largely overlooked ecological function. Quantitatively significant DOM processing may not be the exclusive function of the microbial world on coral reefs; sponges transform DOM to biomass, and thus retain and store organic matter in the reef system.

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Bacterial conjugation constitutes a major horizontal gene transfer mechanism for the dissemination of antibiotic resistance genes among human pathogens. Antibiotic resistance spread could be halted or diminished by molecules that interfere with the conjugation process. In this work, synthetic 2-alkynoic fatty acids were identified as a novel class of conjugation inhibitors. Their chemical properties were investigated by using the prototype 2-hexadecynoic acid and its derivatives. Essential features of effective inhibitors were the carboxylic group, an optimal long aliphatic chain of 16 carbon atoms, and one unsaturation. Chemical modification of these groups led to inactive or less-active derivatives. Conjugation inhibitors were found to act on the donor cell, affecting a wide number of pathogenic bacterial hosts, including Escherichia, Salmonella, Pseudomonas, and Acinetobacter spp. Conjugation inhibitors were active in inhibiting transfer of IncF, IncW, and IncH plasmids, moderately active against IncI, IncL/M, and IncX plasmids, and inactive against IncP and IncN plasmids. Importantly, the use of 2-hexadecynoic acid avoided the spread of a derepressed IncF plasmid into a recipient population, demonstrating the feasibility of abolishing the dissemination of antimicrobial resistances by blocking bacterial conjugation.

Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of P. yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC 50 value 6.6. μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC 50 value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescense analysis (IC 50 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory against the PfFAS-II enzymes PfFabI and PfFabZ with IC 50 values of 0.38 and 0.58 μg/ml (IC 50 control drugs 14 and 30 ng/ml) respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC 50 values 3.7-31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC 50 20.2 μg/ml), and Leishmania donovani (IC 50 values 4.1-13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature and calculated pharmacokinetic properties suggest that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes.

27514a-Carboxy-10s-hydroxy-ls,lB-dimet hyl-1 1-met hylene-8sB,9B-o~d~(~,sa)-tricyclo[ 6.3.O.P]undecane (Hirsutic Acid

The fatty acid compositions of the hyperthermophilic microorganisms Thermotoga maritima and Pyrococcus furiosus were studied and compared. A total of 37 different fatty acids were identified in T. maritima, including the novel 13,14-dimethyloctacosanedioic acid. In contrast, a total of 18 different fatty acids were characterized, as minor components, in P. furiosus, and these included saturated, monounsaturated, and dicarboxylic acids. This is the first report of fatty acids from an archaeon.Hyperthermophiles are a recently discovered group of microorganisms that have the remarkable property of growing at temperatures near and even above 100ЊC (15). Almost 20 different genera of hyperthermophiles are currently known (2), all but two of which are classified as archaea (formerly archaebacteria [17]) rather than as bacteria. The two exceptions are Thermotoga and Aquifex (2). Although a variety of enzymes and proteins have been purified from the hyperthermophiles (1), there has been no comparison of the fatty acid compositions of archaeal and bacterial species reported. In this paper, we present such a comparison by using Thermotoga maritima (9) as the bacterial representative and Pyrococcus furiosus (7) as the archaeal one. Although they represent different domains of life, these two organisms have many metabolic features in common. They are both strictly heterotrophs that obtain energy for growth by the fermentation of carbohydrates to yield organic acids, CO 2 and H 2 . In addition, both reduce elemental sulfur to H 2 S.T. maritima was first isolated from geothermally heated sea vents in Italy (9). Initially, it was found that 7% of its lipids were C 12 to C 18 fatty acids, 10% were symmetrical C 30 to C 34 long-chain dicarboxylic acids with central dimethyl branching, and 83% were unidentified hydrophobic compounds (9). Only one dicarboxylic acid was further characterized as 15,16-dimethyltriacontanedioic acid, known by the trivial name of diabolic acid (11). The related 15,16-dimethyl-30-glyceryloxytriacontanoic acid has also been characterized in T. maritima (5). The C 30 diabolic acid is not unique to T. maritima, since it was previously identified in Butyrivibrio spp., bacteria occurring in the rumen (11). Further work has shown that Butyrivibrio diabolic acids function as linkers between two alkenylglycerophosphoglycerols or one alkenylglycerophosphoglycerol and an alkenylglycerogalactose (4). Such complex lipids have not been isolated from T. maritima, but a novel series of glycolipids with a rare ␣(134) diglucosyl structure has been reported (13).In contrast to T. maritima, not much is known about the lipid composition of P. furiosus, but archaea mainly biosynthesize isopranyl ether lipids instead of the normal fatty acids and phospholipids found in most organisms (12). For example, 90% of the lipids of the closely related archaeon P. woesei is the diether 2,3-di-O-phytanyl-sn-glycero-1-phosphoryl-1Ј-myo-L-inositol (12). To the best of our knowledge, there is no report on fatty acids from a Pyrococcus sp....

Voluntary running is a robust inducer of adult hippocampal neurogenesis. Given that fatty acid synthase (FASN), the key enzyme for de novo fatty acid biosynthesis, is critically involved in proliferation of embryonic and adult neural stem cells, we hypothesized that FASN could mediate both exercise-induced cell proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhancement of spatial learning and memory. In 20 week-old male mice, voluntary running-induced hippocampal-specific upregulation of FASN was accompanied also by hippocampal-specific accumulation of palmitate and stearate saturated fatty acids. In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v.) microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze. Unlike the vehicle-injected mice, the C75 group adopted a non-spatial serial escape strategy and displayed delayed escape latencies during acquisition and memory tests. Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ. Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis.