Fig 5 - available via license: CC BY
Content may be subject to copyright.
Fatty acid supplementation can overcome growth inhibition by PYRC and EQI treatment in S. aureus. S. aureus was grown in the presence of drug in LB+BSA (No FAs; black circle), LB+BSA plus a15:0/a17:0 (500 μM, 2:1 ratio of a15:0 to a17:0; red triangle), or LB+BSA plus 18:1Δ9 (500 μM; blue square). Mean data of two independent experiment run in triplicate are shown ± standard error of the mean. Significance was determined using a two-tailed, unpaired t test. � , p < 0.05 (No FAs vs a15:0/a17:0): †, p < 0.05 (No FAs vs 18:1Δ9). A) Percent growth of S. aureus in the presence of PYRC. B) Percent growth of S. aureus in the presence of EQI.
Source publication
Antimicrobial resistance is a growing global health and economic concern. Current antimicrobial agents are becoming less effective against common bacterial infections. We previously identified pyrrolocins A and C, which showed activity against a variety of Gram-positive bacteria. Structurally similar compounds, known as pyrrolidinediones (e.g., TA-...
Contexts in source publication
Context 1
... a study in which S. aureus was treated with fatty acid synthesis inhibitors, 50% of endogenous fatty acids were replaced following growth in media supplemented with oleic acid [22]. We found that SBCFAs (a15:0 and a17:0) and oleic acid (OA; 18:1Δ9) significantly rescued bacterial growth against PYRC and EQI treatments, consistent with the idea that PYRC and EQI target fatty acid biosynthesis ( Fig 5). When EQI or PYRC were tested for activity against an acetyl-CoA carboxylase (ACC) deficient S. aureus mutant (ΔaacD; generously provided by Dr. Rock); no effect was observed. ...
Context 2
... and colleagues restored growth of S. aureus in the presence of an ACC inhibitor by adding exogenous fatty acids, but the growth was not reestablished by fatty acids in the presence of FAS inhibitors [35]. We treated S. aureus with EQI or PYRC in the presence or absence of exogenous fatty acids (a15:0/ a17:0 and 18:1Δ9), demonstrating a recovery very similar to what was observed by Rock and colleagues in the presence of ACC inhibitor (Fig 5). These results implicated ACC as the target of the pyrrolidinedione acid metabolites, EQI and PYRC. ...
Citations
... Equisetin (EQST), a tetramate-containing natural product with antibiotic and cytotoxic activity, was first derived from the terrestrial fungus Fusarium equisetin NRRL 5537 [22]. It was reported that equisetin inhibits bacterial acetyl-CoA carboxylase (ACC) in fatty acid synthesis and affects mitochondrial metabolism [21][22][23][24] suggesting that EQST has an important role in lipid metabolism. ...
... It has previously been reported that EQST, a fungal natural compound, possesses antibiotic and cytotoxic activity by targeting bacterial fatty acid synthesis and mitochondrial metabolism [21][22][23][24]. However, limited information has been available regarding its effects on lipid metabolism at the cellular level in mammals. ...
Obesity has a significant impact on endocrine function, which leads to metabolic diseases including diabetes, insulin resistance, and other complications associated with obesity. Development of effective and safe anti-obesity drugs is imperative and necessary. Equisetin (EQST), a tetramate-containing marine fungal product, was reported to inhibit bacterial fatty acid synthesis and affect mitochondrial metabolism. It is tempting to speculate that EQST might have anti-obesity effects. This study was designed to explore anti-obesity effects and underlying mechanism of EQST on 3T3-L1 adipocytes differentiated from 3T3-L1 cells. Oil Red O staining showed that EQST reduced lipid accumulation in 3T3-L1 adipocytes. Quantitative real-time polymerase chain reaction and Western blot analysis revealed that EQST significantly inhibited expression of adipogenesis/lipogenesis-related genes C/ebp-α, Ppar-γ, Srebp1c, Fas, and reduced protein levels. There was also increased expression of key genes and protein levels involved in lipolysis (Perilipin, Atgl, Hsl), brown adipocyte differentiation (Prdm16, Ucp1), mitochondrial biogenesis (Pgc1α, Tfam) and β-oxidation Acsl1, Cpt1. Moreover, mitochondrial content, their membrane potential ΔΨM, and respiratory chain genes Mt-Co1, Cox7a1, Cox8b, and Cox4 (and protein) exhibited marked increase in expression upon EQST treatment, along with increased protein levels. Importantly, EQST induced expression and activation of AMPK, which was compromised by the AMPK inhibitor dorsomorphin, leading to rescue of EQST-downregulated Fas expression and a reduction of the EQST-increased expression of Pgc1α, Ucp1, and Cox4. Together, EQST robustly promotes fat clearance through the AMPK pathway, these results supporting EQST as a strong candidate for the development into an anti-obesity therapeutic agent.
... Compounds 1 and 2 and their related compounds have been reported to exhibit antibacterial activity against Gram-positive bacteria [2]. The molecular target of 1 and pyrrolocin C, a related compound with the same decalin configuration as 2 [9], has been proposed to be acetyl-CoA carboxylase [28]. Although the configuration of pyrrolocin C is opposite to that of 1 (i.e., the same as that of 2), both compounds possess anti-Staphylococcus activity and would share the same molecular targets. ...
... Although the configuration of pyrrolocin C is opposite to that of 1 (i.e., the same as that of 2), both compounds possess anti-Staphylococcus activity and would share the same molecular targets. Moreover, as was the case for 3 and 4, the cis-decalin isomer of pyrrolocin C had lower antibacterial activity [9,28]. Thus, no significant difference in antibacterial activity between the two trans-decalin compounds with opposite configurations (2S,3R,8S,11R and 2R,3S,8R,11S) was present, whereas a change in the configuration from trans to cis caused a decrease in antibacterial activity. ...
Decalin-containing tetramic acid is a bioactive scaffold primarily produced by filamentous fungi. The structural diversity of this group of compounds is generated by characteristic enzymes of fungal biosynthetic pathways, including polyketide synthase/nonribosomal peptide synthetase hybrid enzymes and decalin synthase, which are responsible for the construction of a linear polyenoyl tetramic acid structure and stereoselective decalin formation via the intramolecular Diels-Alder reaction, respectively. Compounds that differed only in the decalin configuration were collected from genetically engineered mutants derived from decalin-containing tetramic acid-producing fungi and used for a structure-activity relationship study. Our evaluation of biological activities, such as cytotoxicity against several cancer cell lines and antibacterial, antifungal, antimalarial, and mitochondrial inhibitory activities, demonstrated that the activity for each assay varies depending on the decalin configurations. In addition to these known biological activities, we revealed that the compounds showed inhibitory activity against the insect steroidogenic glutathione S-transferase Noppera-bo. Engineering the decalin configurations would be useful not only to find derivatives with better biological activities but also to discover overlooked biological activities.
... Alkaloids are nitrogen-containing compounds with heterocyclic rings that possess various physiological effects in humans and are used in the development of potent drugs to treat various life-threatening diseases (Dey et al., 2020). Some of the important alkaloid compounds (Fig. 3h), namely equisetin, nicotin, and palustrine, isolated from the ethanolic extracts of the sterile aerial stem of E. arvense (Phillipson and Melville, 1960;Ardelean and Mohan, 2008), were reported to have antimicrobial and enzyme activities and have a significant role in regulation of hormone secretion (Yildiz, 2004;Larson et al., 2020). Palustridin, N5-formyl palustrine, and N5-Acetyl palustrine were isolated from the petroleum ether and methanolic extracts of E. palustre (Ardelean and Mohan, 2008;Cramer et al., 2015). ...
Introduction:
The genus Equisetum (Equisetaceae) is cosmopolitan in distribution, with 41 recognized species. Several species of Equisetum are widely used in treating genitourinary and related diseases, inflammatory and rheumatic problems, hypertension, and wound healing in traditional medicine practices worldwide. This review intends to present information on the traditional uses, phytochemical components, pharmacological activities, and toxicity of Equisetum spp. and to analyze the new insights for further study.
Methods:
Relevant literature has been scanned and collected via various electronic repositories, including PubMed, Science Direct, Google Scholar, Springer Connect, and Science Online, from 1960 to 2022.
Results:
Sixteen Equisetum spp. were documented as widely used in traditional medicine practices by different ethnic groups throughout the world. A total of 229 chemical compounds were identified from Equisetum spp. with the major group of constituents being flavonol glycosides and flavonoids. The crude extracts and phytochemicals of Equisetum spp. exhibited significant antioxidant, antimicrobial, anti-inflammatory, antiulcerogenic, antidiabetic, hepatoprotective, and diuretic properties. A wide range of studies have also demonstrated the safety of Equisetum spp.
Conclusion:
The reported pharmacological properties of Equisetum spp. support its use in traditional medicine, though there are gaps in understanding the traditional usage of these plants for clinical experiments. The documented information revealed that the genus is not only a great herbal remedy but also has several bioactives with the potential to be discovered as novel drugs. Detailed scientific investigation is still needed to fully understand the efficacy of this genus; hence, very few Equisetum spp. were studied in detail for phytochemical and pharmacological investigation. Moreover, its bioactives, structure-activity connection, in vivo activity, and associated mechanism of action ought to be explored further.
... Its mechanism is not yet known. Equisetin exemplifies a structure with a breadth of biological activities, among which is the inhibition of bacterial acetyl-CoA carboxylase resulting in failed fatty acid biosynthesis [65]. Its own biosynthesis involves an enzyme-catalyzed ring-forming Diels-Alder cycloaddition [66,67]. ...
The title of this essay is as much a question as it is a statement. The discovery of the β-lactam antibiotics—including penicillins, cephalosporins, and carbapenems—as largely (if not exclusively) secondary metabolites of terrestrial fungi and bacteria, transformed modern medicine. The antibiotic β-lactams inactivate essential enzymes of bacterial cell-wall biosynthesis. Moreover, the ability of the β-lactams to function as enzyme inhibitors is of such great medical value, that inhibitors of the enzymes which degrade hydrolytically the β-lactams, the β-lactamases, have equal value. Given this privileged status for the β-lactam ring, it is therefore a disappointment that the exemplification of this ring in marine secondary metabolites is sparse. It may be that biologically active marine β-lactams are there, and simply have yet to be encountered. In this report, we posit a second explanation: that the value of the β-lactam to secure an ecological advantage in the marine environment might be compromised by its close structural similarity to the β-lactones of quorum sensing. The steric and reactivity similarities between the β-lactams and the β-lactones represent an outside-of-the-box opportunity for correlating new structures and new enzyme targets for the discovery of compelling biological activities.
... Equisetin is an Nmethylserine-derived acyl tetramic acid, first isolated from the deep-sea fungus Fusarium equiseti NRRL 5337 [17,18]. It exerts a robust antibacterial activity against MDR bacteria, especially Gram-positive pathogens, by a novel mode of action involving allosterically binding to biotin carboxylase [19,20]. In addition, equisetin also inhibits HIV-Ι integration and the quorum-sensing in P. aeruginosa [21,22]. ...
... Mar. Drugs 2022,20, 656 ...
Mammalian cells act as reservoirs of internalized bacteria to circumvent extracellular antibacterial compounds, resulting in relapse and reinfection diseases. The intracellular persistence of Staphylococcus aureus renders most traditional antibiotics useless, due to their inadequate subcellular accumulation. To replenish our antibiotic arsenal, we found that a marine-derived compound, equisetin, efficiently eliminates intracellular S. aureus by potentiating the host autophagy and inducing mitochondrial-mediated ROS generation to clear the invading S. aureus. The remarkable anti-infection activity of equisetin was validated in a peritonitis-infected mouse model. The marine product equisetin utilizes a unique dual mechanism to modulate the host–pathogen interaction in the clearance of intracellular bacteria. Thus, equisetin is an inspiring host-acting candidate for overcoming intracellular pathogens.
... Biotin protein ligase has been described as a novel drug target for new antibacterial drugs (Feng et al. 2016;Larson et al. 2020). The protein is involved in fatty acid biosynthesis which is crucial for cell membrane development and maintenance (Salaemae et al. 2011). ...
Clostridioides difficile is the major cause of antibiotic-associated diarrhea in hospitalized patients. The low susceptibility of this pathogen to first-line antibiotics coupled with the recurrence of its infection (CDI) has become a global concern that necessitates the need to explore novel drug targets against this pathogen. In this study, in-silico approaches through pangenome and subtractive genomic analysis were used to predict putative drug targets. A total of 2556 core genes were identified after pangenome analysis of which 173 were predicted to be essential and non-homologous to human host. Further analysis such as virulence effector function, subcellular localization, involvement in metabolic pathways, gene-enrichment analysis, physicochemical properties and druggability of the proteins were done. A total of 5 cytoplasmic proteins were finally predicted as novel putative drug targets. This study contributes immensely to the search of novel drug targets against C. difficile though further experimental validation is highly imperative.
... Previous reports indicate that equisetin functions in eukaryotic cells by affecting mitochondrial metabolism (Freiberg et al., 2004;Quek et al., 2013). Equisetin could affect malonyl-CoA synthesis as an acetyl-CoA carboxylase inhibitor (Freiberg et al., 2004;Larson et al., 2020). HIV integrase is inhibited by equisetin based upon its metal-binding property (Hazuda et al., 1999;Clercq, 2000). ...
The Beibu Gulf harbors abundant underexplored marine microbial resources, which are rich in diversified secondary metabolites. The genera Vibrio is a well-known pathogenic bacterium of aquatic animals. In this study, 22 fungal strains were isolated and identified from the Beibu Gulf coral via the serial dilution method and internal transcribed spacer (ITS) sequence analysis, which were further divided into three branches by phylogenetic tree analysis. The crude extracts of them via small-scale fermentation were selected for the screening of inhibitory activity against Vibrio alginalyticus, Vibrio coralliilyticus, Vibrio harveyi, Vibrio parahaemolyticus, Vibrio owensii, and Vibrio shilonii. The results showed that eight fungal extracts displayed anti-Vibrio activity via the filter paper disk assay. Several of them showed strong inhibitory effects. Then, two tetramic acid alkaloids, equisetin (1) and 5′-epiequisetin (2), were identified from Fusarium equiseti BBG10 by bioassay-guided isolation, both of which inhibited the growth of Vibrio spp. with the MIC values of 86–132 μg/ml. The scanning electron microscope results showed that cell membranes of Vibrio became corrugated, distorted or ruptured after treatment with 1 and 2. Taken together, this study provided eight fungal isolates with anti-Vibrio potentials, and two alkaloid-type antibiotics were found with anti-Vibrio effects from the bioactive strain F. equiseti BBG10. Our findings highlight the importance of exploring promising microbes from the Beibu Gulf for the identification of anti-Vibrio for future antibiotic development.
... Limitations of time and resources are significant barriers to combinatorial therapy investigation because research on drug-drug interactions is required to determine whether the combinatorial therapy is synergistic or antagonistic, and promising combinations may be pathogen-specific. The outer membrane-permeabilizing agent polymyxin B potentiates the antibacterial activity of the AccC inhibitor equisetin, causing >90% inhibition of E. coli as compared to ~0% inhibition when cells are treated with equisetin alone (74). A high-throughput screen identified 2-aminoimidazoles that reduced the MIC of isoniazid and restored isoniazid sensitivity to drug-tolerant M. tuberculosis attached microbial communities (3). ...
Antibiotic resistance is a serious public health concern, and new drugs are needed to ensure effective treatment of many bacterial infections. Bacterial type II fatty acid synthesis (FASII) is a vital aspect of bacterial physiology, not only for the formation of membranes but also to produce intermediates used in vitamin production. Nature has evolved a repertoire of antibiotics inhibiting different aspects of FASII, validating these enzymes as potential targets for new antibiotic discovery and development. However, significant obstacles have been encountered in the development of FASII antibiotics, and few FASII drugs have advanced beyond the discovery stage. Most bacteria are capable of assimilating exogenous fatty acids. In some cases they can dispense with FASII if fatty acids are present in the environment, making the prospects for identifying broad-spectrum drugs against FASII targets unlikely. Single-target, pathogen-specific FASII drugs appear the best option, but a major drawback to this approach is the rapid acquisition of resistance via target missense mutations. This complication can be mitigated during drug development by optimizing the compound design to reduce the potential impact of on-target missense mutations at an early stage in antibiotic discovery. The lessons learned from the difficulties in FASII drug discovery that have come to light over the last decade suggest that a refocused approach to designing FASII inhibitors has the potential to add to our arsenal of weapons to combat resistance to existing antibiotics.
Expected final online publication date for the Annual Review of Microbiology, Volume 76 is September 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... EQST exhibits favorable medicinal potential since that EQST achieve antibacterial effect by inhibiting de novo synthesis of fatty acids 99 and inhibiting quorum sensing 100 , and external application of EQST can effectively promote wound healing by inhibiting bacteria 32 . Our results also demonstrate that EQST confers J o u r n a l P r e -p r o o f potent anti-obesity activity. ...
Obesity is increasingly prevalent globally, searching for therapeutic agents acting on adipose tissue is of great importance. Equisetin (EQST), a meroterpenoid isolated from a marine sponge-derived fungus, has been reported to display antibacterial and antiviral activities. Here, we revealed that EQST displayed anti-obesity effects acting on adipose tissue through inhibiting adipogenesis in vitro and attenuating HFD-induced obesity in mice, doing so without affecting food intake, blood pressure or heart rate. We demonstrated that EQST inhibited the enzyme activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a therapeutic target of obesity in adipose tissue. Anti-obesity properties of EQST were all offset by applying excessive 11β-HSD1’s substrates and 11β-HSD1 inhibition through knockdown in vitro or 11β-HSD1 knockout in vivo. In the 11β-HSD1 bypass model constructed by adding excess 11β-HSD1 products, EQST’s anti-obesity effects disappeared. Furthermore, EQST directly bond to 11β-HSD1 protein and presented remarkable better intensity on 11β-HSD1 inhibition and better efficacy on anti-obesity than known 11β-HSD1 inhibitor. Therefore, EQST can be developed into anti-obesity candidate compound, and this study may provide more clues for developing higher effective 11β-HSD1 inhibitors.
... [6,7,8] Several methods have been evaluated to diminish the use of chemical fungicides, including bio-fungicides like microorganisms, plant extracts and metabolites, minerals, microbial metabolites, essential oils, ions. [9] Pyrrolidin-2-one or γ-lactam 1 is a heterocyclic moiety widespread in many natural compounds [10] ( Figure 1-Cotinine, [11] Equisetin [12,13] and Lactacystin [14,15] ). This motif can be found in metabolites from organisms such as fungi, bacteria, plants or even animals. ...
As new environmentally friendly and effective antifungal agents are deeply need, efficient ecofriendly strategies were designed to access two series of compounds inspired from natural g‐lactams. Designed compounds were fully characterized and evaluated as antifungal candidates against Zymoseptoria tritici , the main pathogen on wheat crops. The targeted derivatives were prepared from natural resources using green solvents, simple procedures, and limited purification steps. These bio‐inspired compounds revealed as good candidates for further development of efficient crop protection products. Indeed, the HIT compounds exhibited IC 50 around 1 µg/mL and were more active than the references tebuconazole and bixafen towards some multidrug‐resistant strains. Two dozen of derivatives have been obtained for each series and allowed to establish early structure‐activity relationships useful for the development of next generation g‐lactam derivatives with improved efficacy.
