Dengue fever causes significant human illness and mortality worldwide, especially in the tropics and subtropical regions . Dengue fever, also known as a break-bone fever, is an infectious disease caused by the tropical dengue virus [2, 3]. The disease is transmitted by mosquitoes of the genus Aedes, especially the species Aedes aegypti L. (Diptera: Culicidae) . Typical symptoms of the disease are fever, headache, muscle and joint pain, in addition to a characteristic rash similar to measles . The incidence of dengue has grown rapidly, by a factor of thirty since the 1960’s. Between 1960 and 2010, human population growth and migration increased and 50-100 million people were infected with dengue fever each year. Prevention of the disease is based on controlling the mosquito population vector and protection from contact with the residents of endemic areas . One dengue vaccine (CYD-TDV, or Dengvaxia®) has been registered and several of other dengue vaccine candidates are in clinical development. The two most advanced candidates are currently under evaluation in Phase 3 trials .
Ae. aegypti is also one of the vectors of Zika virus . The clinical presentation of Zika fever is nonspecific and can be misdiagnosed as the first infections were associated with flu-like symptoms . In addition, severe neurological complications were reported in the French Polynesian outbreak in 2013 and 2014, and later a dramatic increase in congenital malformations (microcephaly) were reported from Zika emergence in Brazil . Although there is no vaccine to control the Zika virus, several attempts are in the development phase. Preventative measures are therefore the same as cited above for Ae. aegypti-borne diseases .
The main method of control of Ae. aegypti is the elimination of its habitat [10, 11], which can be achieved in disease-endemic areas by emptying any standing containers of water. The most widely used larvicide worldwide for mosquitoes is Bacillus thuringiensis israelensis (Bti). Application of Bti has been used to reduce the number of mosquitoes, including Ae. aegypti [10, 11]. Another method is the use of animal species that prey on the vector, such as Poecilia reticulata or copepods that feed on their larvae or the immature stages of Toxorhynchites spp. that can consume mosquito larvae in tree crevices. Wolbachia-infected Ae. aegypti for dengue fever control can be another biocontrol approach . Repellents applied to skin or clothing are also recommended as a means of personal protection against biting arthropods . Insecticides, such as pyrethroids and organophosphates  can also be used. Synthetic and natural compounds, including pyrethroids, are approved by the EPA (Environmental Protection Agency) for use as repellents, but only when applied to clothing . However, use of pyrethroids for control of a wide range of arthropods has given rise to environmental and health concerns [15-17]. These problems were increased by the development of resistance against pyrethroids and other insecticides, and this resistance has prompted the design of alternative control strategies [16-18]. Therefore, great effort has been expended on the development of pest controls using naturally occurring compounds such as secondary plant and fungal metabolites. Many naturally occurring repellents and insecticides have the potential for development into useful products with lowered risk to mammals and the environment [19-21]. As a consequence, the search for new anti-dengue agents from medicinal plants has become more urgent than in the past and the results of these studies were recently reviewed [12, 22, 23].
Microbial phytotoxins are a source of natural products and have been extensively investigated in agrochemical discovery by Evidente and coauthors [24-31]. For example, some fungal phytotoxins such as cyclopaldic acid, seiridin, sphaeropsidin A and papyracillic acid were evaluated for their biting deterrent and larvicidal activities against 1st instar Ae. aegypti . Furthermore, papyracillic acid isolated from a solid culture of Ascochyta agropyrina var. nana showed potential herbicide activity against quack grass Elytrigia repens . These promising results stimulated the preparation of semisynthetic derivatives of papyracillic acid and investigation of the structure-activity relationships of active deterrent compounds in a subsequent study .
In our continuing effort to find new natural mosquitocidal agents, several fungal and plant metabolites belonging to diverse structural classes, including; alkaloids, anthracenes, azoxymethoxytetrahydropyrans, cytochalasans, 2,5-diketopiperazines, isochromanones, naphthoquinones, small organic acids and their methyl esters, sterols, and terpenes were evaluated against Ae. aegypti.
All the metabolites used to test for insecticidal activity against Ae. aegypti are shown in Figure 1 and reported in Table 1, which also contains the compound source and the corresponding literature [28, 29, 34-46]. Purity of each compound was ascertained by TLC, NMR and ESI-MS using established methods. 1H NMR spectra were recorded at 400 MHz, on Bruker spectrometer (Bruker BioSpin GmbH., Karlshrue, Germany), using the same solvent as used for the internal standard. ESI MS spectra were recorded on Agilent Technologies 6120 quadrupole LC/MS instrument (Agilent instruments, Milan, Italy); analytical and preparative thin layer chromatography (TLC) were performed on silica gel (Kieselgel 60, F254, 0.25 and 0.5 mm respectively) plates (Merck, Darmstadt, Germany); the spots were visualized by exposure to UV light or by spraying with 10% H2SO4 in CH3OH and then 5% phosphomolybdic acid in EtOH, followed by heating at 110°C for 10 min.
Aedes aegypti larvae and adults used in this study were from laboratory colonies maintained at the USDA-ARS, CMAVE, Gainesville, Florida, USA. The “Orlando” strain was collected near Orlando, Florida, USA in 1952 and has been in continuous laboratory colony for 65 years. Rearing procedures are standardized and have been described previously . Technical-grade permethrin (Chem Service, West Chester, PA, USA), a combination of 46.1% cis and 53.2% trans isomers, was used as the positive control in all assays.
2.2.1 Larvicidal activity
For larval bioassays (Fig. 2), all compounds were initially diluted in DMSO to make 100 µg/µL. Mortality was determined in the larval assays at four different concentrations (1.0, 0.5, 0.25, and 0.1 µg/µL) in a final volume of 200 µL of larval rearing media that contained five 1st instar Ae. aegypti larvae. Larval assays were performed using a 96-well plate and the larvae were provided with 10 µL of the supernatant from a 2% solution of 1:1 alfalfa powder: pig chow. For each assay, a positive control of permethrin and a negative control of DMSO was included. Mortality data were recorded 24 hours post-exposure. Assays were repeated at least three times on different days.
2.3.2 Adulticidal activity
To determine the toxicity of each sample against adult female Ae. aegypti, samples were initially diluted to a 10% DMSO solution that was subsequently serially diluted 1:10 in acetone. Mosquitoes were anesthetized on ice and groups of 10 females sorted into individual plastic cups. Application of 0.5 µL of the sample solution was applied to dorsal thorax using a Hamilton 700 series syringe and a PB600 repeating dispenser (Thermo Fisher Scientific, Hampton, NH, USA) at a discriminating dose of 5 µg/mosquito. After treatment, mosquitoes were kept in plastic cups and supplied with 10% sucrose solution (Fig. 3). Mortality data were recorded 24 hours post-exposure. Assays were repeated at least three times on different days. For each assay, a positive control of permethrin and a negative control of acetone was included. Statistical analysis for both assays was performed in SigmaPlot.v13 using the best fit sigmoidal plot with the minimum and maximum constrained to 0% and 100%, respectively.
LC50 and LD50 values and 95% confidence intervals (95% CI) were determined for compounds that produced ~80% mortality at the discriminating dose in both larval and adult assays respectively. This was accomplished by using a descending dose series and replicated at least three times. Values were determined by plotting dose-mortality data to a 4-parameter logistic sigmoidal non-linear regression as implemented by SigmaPlot v13.
3 Results and Discussion
The metabolites isolated from bacteria, fungi, and plants belong to several different classes of natural compounds (Table 1) were investigated for the first time to evaluate them as new insecticidal agents against Ae. aegypti. In larval bioassays, mortality was determined at four final concentrations, 1.0, 0.5, 0.25 and 0.1 µg/µL. Out of the 23 compounds (Fig. 1), only three compounds, cytochalasin A (6), gliotoxin (9) and 2-methoxy-1,4-naphthoquinone (15), produced over 80% mortality (Table 2) and subsequently, dose-response bioassays were performed. Compound 9 showed the highest mortality with an LC50 of 0.0257 ± 0.001 µg/µL and followed by compounds 15 (LC50 = 0.0851 ± 0.0012 µg/µL) and 6 (LC50 = 0.0854 ± 0.0019 µg/µL) (Table 2).
In adult bioassays, compounds were tested at the pre-screening dose of 5 µg/mosquito and only four compounds, α-costic acid (4), fusaric acid (8), gliotoxin (9) and 3-nitropropionic acid (16), demonstrated mortality between 83-97% (Table 2). Based on this initial screening activity data, LD50 bioassays were conducted and compound 8 was the most effective compounds with an LD50 value of 0.8349 ± 0.0118 µg/mosquito and followed by compounds 16 (LD50 value = 1.6641 ± 0.0494 µg/mosquito), 4 (LD50 value = 2.547 ± 0.0835 µg/mosquito), 9 (LD50 value= 2.79 ± 0.1197 µg/mosquito) (Table 2).
Among the most active compounds, gliotoxin (9) possessed the best larvicidal activity, whereas fusaric acid (8) demonstrated the greatest adulticidal activity. Compounds chloromonilicin (3), a-costic acid (4), fusaric acid (8), inuloxin A (13) and 3-nitroprpionic acid (16) showed >90% mortality at the 1.0 µg/µL; however, the activity declined quickly as the compound was diluted. In adult bioassays, compounds (20), pyripyropene A (18), pyripyropene E (19), haemanthidine (11), sphaeropsidin C (21), haemanthamine (10) and cytochalasin A (6) exhibited moderate activity and weak activity was displayed by buphanamine (1), chloromonilicin (3), cytochalasin B (7), inuloxin C (14) and 6-hydroxymellein (12). There was no correlation between log P values and adult or larval toxicity (Table 2).
Although compounds showing lavicidal and adulticidal activity belong to different classes of natural compounds, such as diketpiperazines, cyochalasans, naphthoquinones and low molecular weight acids, it seems interesting to compare the high activity of cytochalasin A to the near inactivity of cytochalasin B. In this case, the data confirm the importance of the functional group at C-20, as well as the conformational freedom of the macrocycle for this group of natural compounds. Similar structural impacts were previously observed in tests of their phytotoxic, antimicrobial, cytotoxic, and zootoxic activities [27, 48-52]. Recently, Van Goietsenoven et al.  studied the structure activity relationships (SAR) of eight natural and three hemisynthetic derivatives of cytochalasins and they found that the presence of the hydroxy group at C-7, the functional group at C-20, and the conformational freedom of the macrocyclic ring appeared to also be important structural features for the inhibitory effect on cancer cells.
The compounds buphanamine (1), haemanthamine (10), and haemanthidine (11) belong to the crinine subgroup of the Amaryllidceae alkaloids , and they are defined by the ethane bridge that joins rings B and C, although they have an opposite stereochemistry. As compounds 10 and 11 showed similar adulticidal activity and a lesser larvicidal activity (Table 2), the presence of the hydroxy group on B-ring in 11 seems to not affect these activities. Thus, the lack of larvicidal activity of 1, with respect to that of 10 and 11, could be due to the different stereochemistry of the above cited ethane bridge, which probably affects negatively its interaction with the receptor and perhaps also the different functionalization of the C ring and the presence of the methoxy group at the aromatic A ring.
Inuloxins A (13) and C (14) are both sesquiterpenes, but belong to two different subgroups as germacranes and eudesmanolides, respectively. They are characterized by differences in the carbon skeleton generated from divergent biosynthesis of the common farnesyl-OPP precursor . In our studies, their larvicidal and adulticidal activity was differentiated by inuloxin A (13) being 2-fold more toxic than inuloxin C (14) to Aedes larvae and adults (Table 2).
Current and future insect control mainly relies upon synthetic insecticides; in particular, control of vector-borne diseases would not be effective without these compounds. However, the development of resistance and adverse effect on the environment and human health have become apparent. Natural-based pesticides are often considered a low-risk substitute for conventional chemical insecticides. Though commercial adaptation of natural-based insecticides has been less than expected, continuing scientific studies and growing public awareness are inspiring the development of natural products as new lead insecticides. Pyrethrins are a good example of natural insecticides and their synthetic analogs, pyrethroids, are currently used in numerous formulations for the control of insect pests on animals and in the environment . Microbially produced biopesticides such as abamectins, milbemectin, and spinosyns were developed as insecticides , with abamectins and spinosyns synthetically modified to possess higher efficacy for lepidopteran species . Fungi-derived natural products have been an excellent source of pharmaceuticals as well, such as penicillins, cholesterol-lowering lovastatin, echinocandin B, and immunosuppressive cyclosporin A, proving the importance of investigating fungal sources for new medicines [59, 60]. Also the plants are a very good source of compounds with different biological activities and mode of actions. Recently, three new alkaloids, isolated from the South African plant Nerine sarniensis, showed insecticidal activity against Ae. Aegypti [61, 62].
Results from the current study have stimulated further structure-activity investigations with respect to the mosquitocidal activity of compounds belonging to diketopiperazine, cytochalasan, naphthoquinone and low molecular weight organic acid groups. Further studies are necessary to determine their potential activity against a wide range of insects and these five compounds [a-costic acid (4), cytochalasin A (6), gliotoxin (9), 2-methoxy-1,4-naphthoquinone (15) and 3-nitropropionic acid (16)] could be chemically optimized to improve their insecticidal activity. Finally, microbial metabolites are produced in relatively large quantities by fungi and may be a source of alternatives for insecticidal control of Ae. aegypti.
This study was partly funded by the Deployed War-Fighter Protection Research Program via grants from the U.S. Department of Defense through the Armed Forces Pest Management Board (to JJB and 58-0208-5-001 to JRB). We thank Miss Jessica Louton and Dr. Alden S. Estep (USDA-ARS, CMAVE, Gainesville, FL) for mosquito bioassays. Prof. A. Evidente is associated to Istituto di Chimica Biomolecolare, CNR, Pozzuoli, Italy.
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Published Online: 2017-06-14
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