Abstract
Actinobacteria are the main producers of bioactive natural products essential for human health. Although their diversity in the atmosphere remains largely unexplored, using a multidisciplinary approach, we studied here 27 antibiotic producing Actinobacteria strains, isolated from 13 different precipitation events at three locations in Northern and Southern Spain. Rain samples were collected throughout 2013–2016, from events with prevailing Western winds. NOAA HYSPLIT meteorological analyses were used to estimate the sources and trajectories of the air-mass that caused the rainfall events. Five-day backward air masses trajectories of the diverse events reveals a main oceanic source from the North Atlantic Ocean, and in some events long range transport from the Pacific and the Arctic Oceans; terrestrial sources from continental North America and Western Europe were also estimated. Different strains were isolated depending on the precipitation event and the latitude of the sampling site. Taxonomic identification by 16S rRNA sequencing and phylogenetic analysis revealed these strains to belong to two Actinobacteria genera. Most of the isolates belong to the genus Streptomyces, thus increasing the number of species of this genus isolated from the atmosphere. Furthermore, five strains belonging to the rare Actinobacterial genus Nocardiopsis were isolated in some events. These results reinforce our previous Streptomyces atmospheric dispersion model, which we extend herein to the genus Nocardiopsis. Production of bioactive secondary metabolites was analyzed by LC-UV-MS. Comparative analyses of Streptomyces and Nocardiopsis metabolites with natural product databases led to the identification of multiple, chemically diverse, compounds. Among bioactive natural products identified 55% are antibiotics, both antibacterial and antifungal, and 23% have antitumor or cytotoxic properties; also compounds with antiparasitic, anti-inflammatory, immunosuppressive, antiviral, insecticidal, neuroprotective, anti-arthritic activities were found. Our findings suggest that over time, through samples collected from different precipitation events, and space, in different sampling places, we can have access to a great diversity of Actinobacteria producing an extraordinary reservoir of bioactive natural products, from remote and very distant origins, thus highlighting the atmosphere as a contrasted source for the discovery of novel compounds of relevance in medicine and biotechnology.
Introduction
In nature, members of the Phylum Actinobacteria continue to be the main producers of structurally diverse bioactive natural products, essential for human health. Among Actinobacteria, species of the Streptomyces genus are the most prolific source of novel compounds of medical and industrial relevance as antibiotic and anticancer drugs urgently needed to overcome clinical resistance and toxicity problems. Although traditionally considered soil bacteria, there is increasing evidence that Streptomyces species are ubiquitous, being present not only on terrestrial ecosystems, but also in some of the most extreme and less explored environments on our planet such as the oceans and the atmosphere.
New trends in drug discovery include the search for novel bioactive Actinobacteria in unexplored or underexplored environments. Previous reports in oceanic and atmospheric environments of the Cantabrian Sea region (North Spain, Northeast Atlantic) revealed that phylogenetically diverse Actinobacteria, with a great pharmacological potential, are widespread among intertidal and subtidal seaweeds (Braña et al., 2015; Sarmiento-Vizcaíno et al., 2016) and also among deep-sea coral reefs ecosystems (Sarmiento-Vizcaíno et al., 2017b), where a novel barotolerant actinobacterium, Myceligenerans cantabricum, was isolated (Sarmiento-Vizcaíno et al., 2015). Some of these marine strains were the source of nine new biologically active natural products with antibiotic properties against clinically relevant antibiotic resistant pathogens and cytotoxic activities toward diverse human cancer cell lines (Braña et al., 2017a, b; Sarmiento-Vizcaíno et al., 2017b; Ortiz-López et al., 2018; Rodríguez et al., 2018).
Strains belonging to three Streptomyces species widespread among these coastal and deep-sea habitats (Streptomyces cyaneofuscatus, Streptomyces carnosus, and Streptomyces albidoflavus) were also isolated from different cloud precipitation events happened in the Cantabrian Sea Coast (Braña et al., 2015; Sarmiento-Vizcaíno et al., 2016). Since then, atmospheric precipitations (hailstone, rainwater and snow) were used as natural sampling tools for the study of actinobacterial diversity in the atmosphere. Bioactive strains corresponding to about 3–4% of known Streptomyces species were isolated after precipitations and found to produce a great number of natural products with different biological activities, mainly as antimicrobial and anticancer agents (Sarmiento-Vizcaíno et al., 2018). These atmospheric-derived strains also produced 38 molecules not found in Natural products databases, thus revealing the atmosphere as a novel and promising source for natural product discovery.
Based on previous observations of cultivable Streptomyces species isolated in recent years from different precipitation events on the Cantabrian coast, an atmospheric dispersal model was proposed to explain the cosmopolitan distribution of highly halotolerant Streptomyces species (Sarmiento-Vizcaíno et al., 2016). According to this model, coupled to the Earth’s hydrological cycle, marine bioaerosols forming clouds contribute to the transfer of Streptomyces from oceans into the atmosphere, were they travel dispersed by winds, falling down to the earth by precipitation. Further support for this model came from a culture-independent approach, which reported Actinobacteria among the most dominant phyla in atmospheric precipitations in Japan, also showing seasonal variations in correlation with estimated air mass trajectories (Hiraoka et al., 2017). Connections between oceans, clouds and atmosphere, and their relevance in atmospheric chemistry and climate were addressed through the study of sea spray aerosols (Cochran et al., 2017). Actinobacterial transfer into sea spray aerosols in an experimental ocean-atmosphere mesocosm was also reported (Michaud et al., 2018).
In a culture dependent approach, we provide here further insights into the phylogenetic and secondary metabolic diversity of bioactive atmospheric Actinobacteria isolated from rainwater in precipitations events from Westerly winds in Spain over 4 years’ time. This approach involved rainwater sampling from different locations in Spain, meteorological analyses, taxonomical and phylogenetic analyses with identification at species level. Antimicrobial assays, metabolic profiling and LC-UV-MS analyses of compounds produced were used to assess the Actinobacteria biosynthetic diversity.
Materials and Methods
Sampling of Atmospheric Precipitations
Atmospheric precipitations samples, including rainwater, hailstone and snow were collected within years 2013–2016 at the North of Spain, at the Cantabrian Sea coastal region of Asturias (Figure 1). This is a remarkably wet and rainy region, whose climate is under the influence of the Atlantic Ocean. Samples of 2–3 mL were taken in sterile recipients at the localities of Gijón (43° 32′ N, 5° 39′ W), and Oviedo (43° 21′ N, 5° 52′ W) and plated on selective agar media as previously described (Braña et al., 2015; Sarmiento-Vizcaíno et al., 2016). An additional rain sample (50 mL) was collected in 2016, in Seville (37° 23′ N, 5° 59′ W), Andalusia, South of Spain. Seville has a Mediterranean climate and is considered one of the warmest cities in continental Europe. During all precipitation events sampled here the prevailing wind direction has been Western.
FIGURE 1
Sampling locations in Spain. Overview of the European Seas (Atlantic Ocean). Stars indicate the sampling locations in Northern and Southern Spain.
Isolation of Actinobacteria Strains and Culture Media
A collection of cultivable Actinobacteria strains were obtained after plating of precipitation samples on selective agar media, prepared with cycloheximide (80 μg mL–1) as antifungal and nalidixic acid (20 μg mL–1) as anti-Gram negative bacteria, using MOPS BLEB 1/6 (Oxoid) basal medium as previously reported (Sarmiento-Vizcaíno et al., 2016). Two different media either prepared with distilled water or with a supplement of 3.5% NaCl were used in selection plates. After 2–3 weeks of incubation at 28°C, colonies were selected based on different morphological features and pigment production on R5A agar plates. Isolated pure cultures were conserved in 20% glycerol at both −20° and −70°C. For halotolerance studies, MOPS BLEB 1/6 (Oxoid) was used as the basal medium, adding NaCl at 0, 3.5, 7.0, and 10.5% (w/v) final concentrations. R5A medium was used for secondary metabolite production as previously described (Sarmiento-Vizcaíno et al., 2018).
Bioactive Strains Selection
The antimicrobial activities of isolates were determined by agar diffusion methods using the following indicator microorganisms: the Gram-positive bacteria Micrococcus luteus ATCC 14452 and Streptomyces 85E ATCC 55824, the Gram-negative Escherichia coli ESS, and the yeast Saccharomyces cerevisiae var. carlsbergensis as previously reported (Sarmiento-Vizcaíno et al., 2018). Analyses were performed in TSA1/2 (Merck) against bacteria and in Sabouraud 1/2 (Pronadisa) against yeast. For antibiotic production Actinobacteria cultures were routinely cultured. Figure 2 shows an example of bioassays performed against Micrococcus luteus as indicator bacteria. Agar plugs of 7 mm diameter from Actinobacteria cultures on solid R5A medium (Figure 2A) were assay for initial selection of bioactive isolates. Also Kirby-Bauer based test using with 6-mm-diameter AA Discs (Whatman), loaded with ethyl acetate extracts of bioactive isolates, were performed (Figure 2B). Agar plugs assays detect all diffusible compounds produced by actinobacterial strains, both polar and apolar, whereas the AA discs bioassays only detect diffusible apolar molecules which were extracted with ethyl acetate.
FIGURE 2
Bioassay diffusion assays. Micrococcus luteus was used as indicator microorganism. The zones of complete inhibition are measured as the diameters in mm. (A) Agar plugs. (B) AA discs loaded with ethyl acetate extracts of the isolates.
Air Mass Backward Trajectories Analyses
To estimate the long-range transport journey of air masses that originated the precipitation events herein studied, backward trajectories were generated using the HYSPLIT model (Hybrid Single Particle Lagrangian Integrated Trajectory) from the Global Data Assimilation System of National Oceanic and Atmospheric Administration, United States (Stein et al., 2015). To track the transport pathways of air masses and determine the origin of diverse air parcels, 5-day backward trajectories (used generally in bioaerosol studies) were obtained using the NOAA model.1 To find out the trajectories of atmospheric air masses, the sampling locations were used as the backward trajectory start point with altitudes over the sea level of 30, 1,000 and 3,000 m (Gijón), as previously reported (Sarmiento-Vizcaíno et al., 2018); 300, 1,000, and 3,000 m (Oviedo) and 7, 1,000, and 3,000 m (Seville).
16S RNA Analysis Identification and Phylogenetic Analysis
For taxonomic identification of the strains, DNA was extracted with a microbial isolation kit (Ultra Clean, MoBio Laboratories, Inc.) and standard methods were used for checking the purity (Russell and Sambrook, 2001). Partial 16S rRNA gene sequences of the bacterial strains were obtained by using the 616V (forward) and 699R (reverse) primers (Arahal et al., 2008) in PCR amplification as previously described (Braña et al., 2015). The nucleotide sequences were compared to sequences in databases using the BLAST program (Basic Local Alignment Search Tool) against the NCBI (National Centre for Biotechnology Information), submitted and deposited in the EMBL sequence database with accession numbers LR702033-LR702059. Phylogenetic analysis of the strains based on 16S rRNA sequences was performed as previously reported (Sarmiento-Vizcaíno et al., 2018).
Chromatographic Analysis
Plugs of R5A plates (about 7 mL) were extracted using ethyl acetate in neutral and acidic (1% v/v formic acid) conditions. After evaporation, the organic fraction residue was redissolved in 100 μL of a mixture of DMSO and methanol (50:50). The analyses of the samples were performed by reversed phase liquid chromatography as previously described (Braña et al., 2015; Sarmiento-Vizcaíno et al., 2016).
Identification of Compounds by LC-UV-Vis and LC-UV-HRMS Analyses
Samples were first analyzed and evaluated using an in-house HPLC-UV-Vis database. LC-UV-HRMS analyses were carried out as previously reported (Pérez-Victoria et al., 2016; Sarmiento-Vizcaíno et al., 2018) and major peaks in each chromatogram were searched against the MEDINA’s internal database and also against the Dictionary of Natural Products (DNP) (Chapman & Hall/CRC, 2015).
Results
Isolation and Characterization of Bioactive Atmospheric Actinobacteria by Sampling Multiple Precipitation Events in Spain
The strains herein studied were obtained from a unique Actinobacteria collection generated, during 4 years’ time frame (2013–2016) from diverse atmospheric precipitation events in Spain, as previously reported (Sarmiento-Vizcaíno et al., 2018). After a dereplication process involving phenotypical features, antibiotic activity and also meteorological analyses (see next section), 27 morphologically different bioactive strains isolated from rainwater from storm clouds transported by Western winds were selected for this study. Table 1 shows the results of initial antibiotic analyses of selected strains against a panel of indicator microorganisms (bacteria and fungi) by using agar diffusion assays (Figure 2A). The strains were isolated from samples collected in 12 rainfall events, and one hailstone event (A-241) at three different locations in Spain. The three different sampling places are shown in Figure 1. Among the 27 bioactive isolates, 18 were obtained from samples collected in the North Spain (43° N), 12 in the Cantabrian Sea coast (Gijón) and six strains at 28 km inland (Oviedo); finally 9 strains were isolated from a single rainfall event in South Spain (Seville, 37° N).
TABLE 1
| Strain | Escherichia coli | Micrococcus luteus | Streptomyces 85E | Saccharomyces cerevisiae |
| A-43 | − | 12 | 11 | − |
| A-50 | − | 22 | 10 | − |
| A-53 | − | 13 | 18 | − |
| A-69 | − | − | 10 | − |
| A-87 | 11 | 24 | 11 | 16 |
| A-139* | 18 | 19 | 13 | − |
| A−167 | − | 14 | 10 | − |
| A-169 | − | − | 11 | − |
| A-171 | − | 11 | 12 | 13 |
| A-178 | − | − | 25 | − |
| A-179 | 13 | 32 | 9 | − |
| A-241 | − | 11 | − | − |
| A-249 | − | − | − | 24 |
| A-250 | 22 | 30 | 29 | 43 |
| A-254 | − | − | 12 | − |
| A-256 | − | 11 | 13 | − |
| A-257 | − | − | 9 | − |
| A-258 | − | 33 | − | − |
| A-260 | − | − | 11 | − |
| A-261 | − | 24 | 20 | − |
| A-262 | − | 16 | 10 | − |
| A-263 | 18 | − | − | − |
| A-265 | − | 14 | 11 | − |
| A-266 | − | 10 | − | − |
| A-268 | − | 10 | 11 | 21 |
| A-269 | − | 15 | 26 | − |
| A-271 | − | 33 | 28 | − |
Antibiotic activities of atmospheric Actinobacteria cultures against a panel of Gram-negative, Gram-positive bacteria and fungi.
The assays were initially performed with agar plugs from cultures and activities were estimated as the zones of complete inhibition (diameter in mm). The asterisk indicates that antibiotic activity was only detected in liquid cultures.
Backward Transport Trajectories Analyses
Meteorological analyses were performed to estimate the sources and trajectories of the different air masses that originated the precipitation events in which the selected strains were isolated. These sources were estimated using 5 days HYSPLIT backward trajectories. As shown in Figure 3, most backward trajectories showed air masses traveled eastward off the Atlantic Ocean toward continental Europe. As estimated, the air masses reaching the three sampling sites in Spain were predominantly of marine origin. In the atmospheric precipitation events herein studied, different air masses were transported by westerly winds (traveling at different altitudes) mainly from the Atlantic Ocean. In some events, that will be further stated, the trajectory also involves long-range transport from continental America, the Arctic Ocean and even the Northern Pacific Ocean, to downwind areas, such as the sampling place in continental Europe.
FIGURE 3
Five-day backward trajectories of air masses generating the storms that arrived at Spain and caused the diverse precipitation events. They were calculated with the NOAA HYSPLIT Model with three different transects with different arriving height as previously reported (Sarmiento-Vizcaíno et al., 2018). The sampling locations were used as the backward trajectory start point with altitudes over sea level of 30, 1,000, and 3,000 m (Gijón), 300, 1,000, and 3,000 m (Oviedo), and 7, 1,000, and 3,000 m (Seville). Sampling places are indicated by the black asterisks.
Taxonomic Identification and Phylogenetic Analyses of Bioactive Isolates
Identification of airborne-derived bioactive strains was determined by sequencing fragments of their 16S rRNA gene. Nucleotide sequences were then deposited in the EMBL database, and corresponding accession numbers are shown on Table 2. Phylogenetic analyses of isolates (Figure 4), based on 16S rRNA gene alignments, demonstrate that all isolates belong to two different genera among the Phylum Actinobacteria, since they share 99–100% identity with known actinobacterial species. As shown in Table 2, the identified strains have their closest homologs in previous species isolated from very diverse oceanic and terrestrial habitats. Among 27 studied isolates, 23 belonged to the Streptomyces genus, as previous reports in this environment. Interestingly, all these species are different from the ones isolated in a hailstone precipitation event from clouds transported by prevalent Northwestern winds (Sarmiento-Vizcaíno et al., 2018), thus suggesting that depending on the wind direction different strains can be isolated.
TABLE 2
| Strain | EMBL A. N. | NaCl% | Closest homolog | A. N. | % homology (bp) | Homolog isolation source | References |
| Nocardiopsis sp. A-43 | LR702033 | 7 | Nocardiopsis alba DSM 43377 | X97883 | 100 (685/685) | Honeybees gut, United States; mushroom compost bioaerosol, Poland | Qiao et al., 2012; Paściak et al., 2014 |
| Streptomyces sp. A-50 | LR702034 | 3.5 | Streptomyces spinoverrucosus NBRC 14228 | AB184578 | 99.8 (985/987) | Marine | Hu et al., 2012; |
| Streptomyces sp. A-53 | LR702035 | 3.5 | Streptomyces phaeofaciens NBRC 13372 | AB184360 | 99.7 (765/767) | Soil, Japan | Okamoto et al., 1986 |
| Streptomyces sp. A-69 | LR702036 | 3.5 | Streptomyces sannanensis NBRC 14239 | AB184579 | 99.7 (971/974) | Fresh water lake habitat, India | Singh et al., 2014 |
| Streptomyces sp. A-87 | LR702037 | 10.5 | Streptomyces cacaoi NBRC 12748 | AB184115 | 100 (993/993) | Cacao beans | Shirling and Gottlieb, 1968 |
| Streptomyces sp. A-139 | LR702038 | 3.5 | Streptomyces daqingensis NEAU-ZJC8 | KF982696 | 99.5 (764/768) | Saline-alkaline soil, China | Pan et al., 2016 |
| Streptomyces sp. A-167 | LR702039 | 7 | Streptomyces heliomycini NBRC 15899 | AB184712 | 99.8 (988/990) | Marine-derived, Saudi Arabia | Wang et al., 2017 |
| Nocardiopsis sp. A-169 | LR702040 | 7 | Nocardiopsis synnemataformans IMMIB D-1215T | Y13593 | 99.3 (987/994) | Marine, terrestrial | Bennur et al., 2015 |
| Streptomyces sp. A-171 | LR702041 | 7 | Streptomyces griseolus NBRC 3415 | AB184768 | 100 (964/964) | Soil, Russia | Grammatikova et al., 2003 |
| Streptomycessp. A-178 | LR702042 | 7 | Streptomyces cyaneofuscatus 2–6 | KJ571029 | 99.7 (959/962) | Marine, terrestrial and atmospheric, Spain | Sarmiento-Vizcaíno et al., 2016; 2018 |
| Streptomyces sp. A-179 | LR702043 | 3.5 | Streptomyces lateritiusLMG 19372 | AJ781326 | 99.8 (969/971) | Soil | Elson et al., 1988 |
| Streptomyces sp. A-241 | LR702044 | 3.5 | Streptomyces collinus NBRC 12759 | AB184123 | 99.9 (710/711) | Soil, Germany | Rather et al., 2013 |
| Streptomyces sp. A-249 | LR702045 | 7 | Streptomyces griseolus 11–11 | KJ571072 | 99.9 (961/962) | Soil | Harder et al., 1991 |
| Streptomyces sp. A-250 | LR702046 | 3.5 | Streptomyces floridae NBRC 15405 | AB184656 | 99.8 (950/952) | Soil, Himalaya | Hussain et al., 2018 |
| Streptomyces sp. A-254 | LR702047 | 3.5 | Streptomyces durmitorensisMS405 | DQ067287 | 99.9 (974/975) | Soil, Serbia and Montenegro | Savic et al., 2007 |
| Nocardiopsis sp. A-256 | LR702048 | 10.5 | Nocardiopsis synnemataformans IMMIB D-1215T | Y13593 | 99.3 (987/994) | Marine, terrestrial | Bennur et al., 2015 |
| Nocardiopsis sp. A-257 | LR702049 | 10.5 | Nocardiopsis synnemataformans IMMIB D-1215T | Y13593 | 100 (1002/1002) | Marine, terrestrial | Bennur et al., 2015 |
| Streptomyces sp. A-258 | LR702050 | 3.5 | Streptomyces graminofaciens NBRC 13455 | AB184416 | 100 (968/968) | Soil, Japan | Fukuchi et al., 1995 |
| Nocardiopsis sp. A-260 | LR702051 | 7 | Nocardiopsis synnemataformans IMMIB D-1215T | Y13593 | 100 (978/978) | Marine, terrestrial | Bennur et al., 2015 |
| Streptomyces sp. A-261 | LR702052 | 7 | Streptomyces albogriseolus DSM 40003 | AY177662 | 100 (977/977) | Sea sediment, China Sea | Cui et al., 2007 |
| Streptomyces sp. A-262 | LR702053 | 7 | Streptomyces griseorubens NBRC 12780 | AB184139 | 100 (965/965) | Soil, China | Xu and Yang, 2010 |
| Streptomyces sp. A-263 | LR702054 | 7 | Streptomyces albus NRRL B-1811 | NR118467 | 100 (990/990) | Atmosphere, soil, marine sediment, Spain | Sarmiento-Vizcaíno et al., 2018; Schleissner et al., 2011; Labeda et al., 2014 |
| Streptomyces sp. A-265 | LR702055 | 3.5 | Streptomyces heliomycini 173574 | EU593729 | 99.7 (978/981) | Marine-derived Saudi Arabia | Wang et al., 2017 |
| Streptomyces sp. A-266 | LR702056 | 7 | Streptomyces cellulosae NRRL B-2889T | DQ442495 | 99.9 (991/992) | Soybean root | Liu et al., 2013 |
| Streptomyces sp. A-268 | LR702057 | 7 | Streptomyces griseolus NBRC 3415 | AB184768 | 99.9 (963/964) | Soil, Russia | Grammatikova et al., 2003 |
| Streptomyces sp. A-269 | LR702058 | 3.5 | Streptomyces sannanensis NBRC 14239 | AB184579 | 99.3 (949/956) | Fresh water lake habitat, India | Singh et al., 2014 |
| Streptomyces sp. A-271 | LR702059 | 3.5 | Streptomyces griseus TBGT | KX269853 | 99.7 (950/953) | Soil; Mariana Trench sediment (10,898 m), Pacific Ocean | Goodfellow and Williams, 1983; Pathom-Aree et al., 2006 |
Phylogenetic diversity of atmospheric-derived bioactive Actinobacteria isolates.
FIGURE 4
Neighbor-joining phylogenetic tree generated by distance matrix analysis of 16S rRNA gene sequences from atmospheric Actinobacteria (Streptomyces and Nocardiopsis) strains (highlighted) and nearest phylogenetic relatives. The numbers on branch nodes indicate bootstrap values (1,000 resamplings; only values > 50% are shown). Bar represents1% sequence divergence.
In addition, isolates belonging to the actinobacterial genus Nocardiopsis were herein identified in two precipitation events. A Nocardiopsis alba homolog, isolated in one of the North sampling places (Gijón), and several Nocardiopsis synnemataformans homologs in the South sampling place (Seville), which differ approximately in 6 latitudinal degrees. Nocardiopsis species were previously reported both in terrestrial and aquatic ecosystems (Bennur et al., 2015; Table 2) and are considered of pharmaceutical and biotechnological relevance due to its ability to produce diverse bioactive secondary metabolites (Bennur et al., 2016; Ibrahim et al., 2018).
A generalized feature of all Actinobacteria here studied is their ability to tolerate high NaCl concentrations, in the range 3.5–10.5% (Table 2). This high halotolerance is in agreement with previous reports within Streptomyces (Sarmiento-Vizcaíno et al., 2018) and in Nocardiopsis species, which are considered as the most abundant halophilic actinobacteria (Hamedi et al., 2013).
Metabolite Profiling Analysis and Identification of Bioactive Secondary Metabolites Produced
Chemical diversity of atmospheric Actinobacteria was assessed by metabolic profiling analyses of ethyl acetate extracts of bioactive strains, obtained in neutral and acidic conditions, screened for antibiotic production using agar diffusion with AA discs (Figure 2B), against a panel of indicator microorganisms (Table 3). Strong antibiotic activities were observed in all extracts, which were particularly active against M. luteus. The extracts were then analyzed for production of secondary metabolites by LC-UV and LC/HRMS analyses in combination with searches in UV and MS databases or the DNP after generation of a molecular formula of each peak based on HRMS results. Most of the strains show complex metabolic profiles producing multiple secondary metabolites in R5A medium (Supplementary Material 1). Figure 5 displays UV210 nm chromatograms corresponding to Nocardiopsis sp. A-256 and Streptomyces sp. A-254 samples.
TABLE 3
| Strain | Escherichia coli | Micrococcus luteus | Streptomyces 85E | Saccharomyces cerevisiae |
| Nocardiopsis sp. A-43 | − | 17/19 | ND | − |
| Streptomyces sp. A-50 | − | 20/19 | ND | − |
| Streptomyces sp. A-53 | −/8 | 14/22 | ND | − |
| Streptomyces sp. A-69 | − | 9/− | ND | − |
| Streptomyces sp. A-87 | 10/9 | 24/24 | ND | 18/15 |
| Streptomyces sp. A-139 | −/18 | −/19 | ND | − |
| Streptomyces sp. A-167 | 13/− | 11/− | − | − |
| Nocardiopsis sp. A-169 | − | − | − | 11/11 |
| Streptomyces sp. A-171 | 18/− | 13/− | 25/26 | − |
| Streptomyces sp. A-178 | 9/10 | 24/19 | 34/21 | − |
| Streptomyces sp. A-179 | − | 10/− | − | − |
| Streptomyces sp. A-241 | − | 30/25 | − | − |
| Streptomyces sp. A-249 | ND | 25/19 | −/10 | 21/19 |
| Streptomyces sp. A-250 | ND | 44/38 | 41/45 | 38/40 |
| Streptomyces sp. A-254 | ND | 22/21 | 28/28 | − |
| Nocardiopsis sp.A-256 | ND | 23/27 | − | 10/13 |
| Nocardiopsis sp. A-257 | ND | 13/14 | − | 10/11 |
| Streptomyces sp. A-258 | ND | 44/44 | − | − |
| Nocardiopsis sp. A-260 | − | −/12 | −/13 | − |
| Streptomyces sp. A-261 | − | 32/30 | −/11 | − |
| Streptomyces sp. A-262 | ND | −/12 | − | − |
| Streptomyces sp. A-263 | 17/18 | −/12 | −/10 | − |
| Streptomyces sp. A-265 | − | 10/15 | − | −/9 |
| Streptomyces sp. A-266 | − | 19/17 | − | − |
| Streptomyces sp. A-268 | − | 24/17 | − | 17/15 |
| Streptomyces sp. A-269 | − | 30/31 | − | − |
| Streptomyces sp. A-271 | −/12 | 23/28 | 30/22 | − |
Antibiotic activities of ethyl acetate extracts of the strains.
Extracts obtained from 7 mL of culture, obtained in neutral and acidic conditions, were resuspended in 50 μL of DMSO-methanol (1:1) from which 15 μL were loaded onto AA discs. The discs were allowed to fully dry before applying to the indicator strain culture.
FIGURE 5
UV210 nm chromatogram of samples A-254 and A-256 with peaks annotated showing dereplicated components. Dereplicated components in sample A-254: (1) Cyclo(prolylvalyl), (2) Cyclo(leucylprolyl), (3) Cyclo(phenylalanylprolyl), (4) Cyclo(prolytryptophyl), (5) C21H38NO9 (related to ravidomycin but with a molecular formula not found in the Dictionary of Natural Products), (6) Deacetylravidomycin, (7) C30H33NO9 (related to ravidomycin but with a molecular formula not found in the Dictionary of Natural Products), (8) Ravidomycin, (9) C40H57NO10 (molecular formula not found in the Dictionary of Natural Products), (10) Tetronomycin, (11) Salaceyin A and (12) Salaceyin B. Dereplicated components in sample A-256: (1) Bisucaberin B, (2) Cyclo(leucylprolyl), (3) Kahakamide A, (4) Endophenazine D, (5) Dihydroxyphenazine, (6) 1-Hydroxy-6-methoxyphenazine, (7) 1-Phenazinecarboxylic acid, (8) Piperafizine B, (9) 3-Benzylidene-6-(4-methoxybenzylidene)-2,5- piperazinedione, (10) 4′-Methoxyneihumicin or XR 330.
Comparative analysis of Streptomyces and Nocardiopsis metabolites detected with natural product databases led to the identification of a total of 169 compounds detected after LC/MS dereplication in the ethyl acetate extracts of all strains metabolites, 139 were identified in the Dictionary of Natural Products, as shown in Table 4. Concerning the biological activity of identified natural products, the most frequent are antibiotics, with a total of 77 antibacterial and antifungal compounds, and also 32 antitumor or cytotoxic agents, 9 antiparasitic, 5 anti-inflammatory, 5 immunosuppressive, 3 antiviral, 2 insecticidal, 1 neuroprotective, 1 antiarthritic,1 plant hormone, 1 siderophore, 1 photoprotective and other products of diverse pharmacological and biotechnological relevance. Some compounds were only found to be produced by strains belonging to the Nocardiopsis genus, such as the antibacterial and anti-Trypanosoma brucei dihydroxyphenazine (A-256, A-257, A-260); the plant hormone Indol Acetic Acid (strain A-260), the antimicrobial kahakamide A, and the immunosuppressant N-(2-hydroxyphenyl)acetamide (A-257), among others.
TABLE 4
| Compound LC/MS | Strain | Biological activities |
| 1-(2-Aminophenyl)ethanone/Phenylacetamide* | A-50 | Antibacterial (Lu et al., 2020) |
| 1-(Hydroxymethyl)-1H-indole-3-carboxylic acid | A-263 | Antifouling (Wang et al., 2020) |
| 1-Hydroxy-6-methoxyphenazine | A-256, A-257 | Antimicrobial? Cook et al., 1971) |
| 10-Oxide-1,8-Phenazinediol/5-Oxide-1,6-Phenazinediol/2,3,7-Phenazinetriol* | A-260 | Antibiotic, antitumor, antimalaria, and antiparasitic activities (Laursen and Nielsen, 2004) |
| 1-Methoxyphenazine | A-257 | Antichlamydial activity (Bao et al., 2020) |
| 1-Phenazinecarboxylic acid | A-169, A-256 | Antifungal (Ye et al., 2010) |
| 1-Phenazinol/2-Phenazinol* | A-260 | Antibiotic (Vivian, 1956; Lu et al., 2013) |
| 2,3,7-Phenazinetriol | A-257 | Antibiotic, antitumor, antimalaria, and antiparasitic activities (Laursen and Nielsen, 2004) |
| 2096D | A-263 | Antiparasitic (Kelly et al., 2020) |
| 2-(Acetoxymethyl)quinoline | A-179 | Potential photoprotective (Sánchez-Suárez et al., 2020) |
| 2-Hydroxy-1-(1H-indol-3-yl)ethanone/1H-Indole-3-carboxy Me ester/3-Indolylacetic acid/Skatole-2-carboxylic acid* | A-241 | Antibacterial and antihelmintic (Himaja et al., 2010) |
| 3-(Hydroxyacetyl)-1H-indole/1H-Indole-3-acetic acid/3-Methyl-1H-indole-2-carboxylic acid/Methyl 1H-Indole-3-carboxylate* | A-69, A169, A-258 | Plant growth regulatory (Arteca, 1996) |
| 35-Amino-32,33,34-bacteriohopanetriol | A-262 | Sterol equivalent (Welander Paula et al., 2009) |
| 3-Benzyl-6-isopropyl-2,5-piperazinedione | A-69 | Unknown |
| 3-Benzylidene-6-(3-hydroxy-2-methylpropylidene)-1-methyl-2,5-piperazinedione/Lansai C* | A-263 | Anti-inflammatory (Thongchai et al., 2010) |
| 3-Benzylidene-6-(4-methoxybenzylidene)-2,5-piperazinedione | A-43, A-256 | |
| 3-Indolylacetic acid | A-260 | Plant hormone (Arteca, 1996) |
| 3-Isobutylidene-6-(4-methoxybenzylidene)-2,5-piperazinedione | A-43 | Antibiotic (Bycroft and Payne, 2013) |
| 4,5-Dihydrogeldanamycin | A-120 | Anticancer (Wu et al., 2012) |
| 4-(5-Formyloxy-3-hydroxyhexyl)-3-methyl-2-oxetanone | A-266 | Unknown |
| 4-Hydroxy-2-methylquinazoline | A-169 | Unknown |
| 5-(6-Methyloctyl)-2(5H)-furanone/5-(6-Methyloctyl)-2(3H)-furanone/2,4,6-Trimethyl-2,4-decadienoic acid/5-Methyl-3-(5-methylheptyl)-2(5H)-furanone/11-Methyl-2,5-dodecadienoic acid* | A-265 | Regulatory signal molecule (He et al., 2010) |
| 5-Hydroxy-5-(hydroxymethyl)hexadecanoic acid | A-262 | Unknown |
| 6-(3-Methyl-2-butenyl)-1H-indole-3-acetaldehyde oxime | A-69 | Unknown |
| 8,10,12-Trihydroxy-2,4-dodecadienoic acid/4-(5-Formyloxy-3-hydroxyheptyl)-3-methyl-2-oxetanone/8,10,12-Trihydroxy-2,4-dodecadienoic acid* | A-271 | Unknown |
| A 88696F/Jerangolide E/3,4-Dihydro-6,8-dihydroxy-3-tridecyl-1H-2-benzopyran-1-one* | A-262 | Antifungal (Hans et al., 1997) |
| Actinonin | A-87 | Anti-Gram-positive and Gram-negative foodborne pathogens (Jung et al., 2017) |
| Actiphenol | A-250 | Antibiotic (Schrey et al., 2012) |
| Aggreceride A | A-262 | Platelet aggregation inhibitor (Omura et al., 1986) |
| Aggreceride B | A-262 | Platelet aggregation inhibitor (Omura et al., 1986) |
| Alaninolysine | A-260 | Unknown |
| Albocycline | A-269 | Antibiotic (Nagahama et al., 1967) |
| Albocycline M1/M2/M4/M5/M7* | A-269 | Antibiotic (Managamuri et al., 2017) |
| Albocycline M3/M6* | A-269 | Antibiotic (Bycroft and Payne, 2013) |
| Albonoursin | A-263 | Antibiotic, antitumor (Fukushima et al., 1973) |
| Alkyldihydropyrone B/Alkyldihydropyrone A/Cyclohomononactic acid/1,3-Dihydroxy-4-methyl-6,8-decadien-5-one* | A-261 | Cytotoxic against the leukemia cell lines (Aizawa et al., 2014); antifungal (Stadler et al., 2001) |
| Alteramide A | A-249, A-268 | Cytotoxic (Shigemori et al., 1992); antifungal (Moree et al., 2014) |
| Alteramide B | A-268 | Antifungal (Ding et al., 2016) |
| Angumycinone A/Boshracin D/Aranciamycin H/Antibiotic YT 127/Gaudimycin A/Hatomarubigin F/Ochracenomicin A* | A-249 | Antibiotic (Igarashi et al., 1995; Kharel et al., 2012; Park et al., 2014); anticancer (Luzhetskyy et al., 2008) |
| Anhydrocycloheximide | A-250 | Antifungal (Sullia and Griffin, 1977) |
| Antibiotic AKD 2A | A-262 | Antibiotic, both antibacterial and antifungal (Akeda et al., 1995) |
| Antibiotic DC 81/Caerulomycin G* | A-262 | Antibiotic (Kim, 2013); Cytotoxic (Fu et al., 2011) |
| Antibiotic FD 991 | A-250 | Antibiotic (Bycroft and Payne, 2013) |
| Antibiotic L 156588 | A-258 | Gastrin and brain cholecystokinin antagonists (Lam et al., 1991) |
| Antibiotic LL-BH872α/Geralcin E/5-Methyl-2-oxo-4-imidazolidinehexanoic acid* | A-171 | Antibiotic (Bianchi et al., 2003) |
| Antibiotic TMC 1A/B * | A-241 | Antibiotic, moderate cytotoxicity (Kohno et al., 1996) |
| Antibiotic TMC 1F | A-241 | Antibiotic, moderate cytotoxicity (Kohno et al., 1996) |
| Antibiotic WS 7338A | A-87 | Antibiotic, endotelin receptor antagonist (Miyata et al., 1992 |
| Antibiotic WS 9326A | A-50 | Tachykinin antagonist (Hashimoto et al., 1992) |
| Antibiotic WS 9326B | A-50 | Tachykinin antagonist (Hashimoto et al., 1992) |
| Aranciamycin E/1-Butyl-3,6,8-trihydroxyanthraquinone-2-carboxylic acid/Fridamycin E/Gaudimycin B/C/β1-Rhodomycinone/Komodoquinone B/2-O-Demethyl-8-demethoxy-10-deoxysteffimycinone* | A-249 | Antitumor (Luzhetskyy et al., 2008); antibiotic (Chen et al., 2011; Bycroft and Payne, 2013) |
| Aranciamycin H/Boshracin D/Angumycinone A/Hatomarubigin F/Gaudimycin A/Antibiotic YT 127/Ochracenomicin A* | A-268 | Antitumor (Luzhetskyy et al., 2008); antibiotic (Igarashi et al., 1995; Kawasaki et al., 2010) |
| Aureusimine B | A-69 | Antibiotic, against Staphylococcus aureus biofilms (Secor et al., 2012) |
| Bafilomycin A1 | A-249 | Vacuolar-type ATPase inhibitor, apoptosis (Tan et al., 2018) |
| Bafilomycin A1/C1* | A-268 | Vacuolar-type ATPase inhibitor, apoptosis (Tan et al., 2018); antifungal (Frändberg et al., 2000) |
| Bafilomycin B1/E* | A-249, A-268 | Antifungal (Frändberg et al., 2000) |
| Bafilomycin C1 | A-249 | Antifungal (Frändberg et al., 2000) |
| Bafilomycin D | A-268 | Antibiotic, cytotoxic (Vu et al., 2018) |
| Benzylcarbamic acid/Streptokordin/2-Acetamidophenol/4-hydroxyphenylacetaldoxime* | A-260 | Cytotoxic (Jeong et al., 2006); antifungal, anti-inflammatory, antitumor, anti-platelet, anti-arthritic (Guo et al., 2020) |
| Christolane C/9-Hydroxystreptazolin/13-Hydroxystreptazolin/Cytoxazone* | A-262 | Antibiotic (Gómez et al., 2012); cytokine modulator (Kakeya et al., 1998) |
| Cyclo(isoleucylprolyl) | A-178, A-241 | Unknown |
| Cyclo(leucylprolyl) | Several strainsA | Antibiotic, cytotoxic (Santos et al., 2015) |
| Cyclo(phenylalanylprolyl) | A-178 | Antibiotic (Santos et al., 2020) |
| Cyclo(prolyltryptophyl) | Several strainsB | Broad spectrum antibacterial activity (Blunt and Munro, 2008) |
| Cyclo(prolyltyrosyl) | A-261 | Cytotoxic (Blunt and Munro, 2008) |
| Cyclo(prolylvalyl) | Several strainsC | Antifungal (Kumar et al., 2014) |
| Cyclo(valylprolyl) | A-139 | Antibacterial (Alshaibani et al., 2017) |
| Cycloheximide | A-250 | Antifungal (Siegel et al., 1966) |
| Deacetylravidomycin | A-254 | Light dependent antitumor and antibiotic (Greenstein et al., 1986) |
| Dihydro-3-hydroxy-3-(1-hydroxy-2,4-hexadienyl)-4-(hydroxymethyl)-2(3H)-furanone/Xanthocidin* | A-262 | Antibiotic (Asahi et al., 1966) |
| Dihydro-4-(hydroxymethyl)-3-(1-hydroxy-5-methylheptyl)-2(3H)-furanone/Dihydro-4-(hydroxymethyl)-3-(1-hydroxy-6-methylheptyl)-2(3H)-furanone/Dihydro-5-(hydroxymethyl)-3-(1-hydroxy-6-methylheptyl)-2(3H)-furanone/Dihydro-4-(hydroxymethyl)-3-(1-hydroxyoctyl)-2(3H)-furanone* | A-171 | Antibiotic (Bycroft and Payne, 2013) |
| Dihydro-5-(6-hydroxy-6-methyloctyl)-2(3H)-furanone/7-Methoxy-4-dodecenoic acid* | A-262 | Unknown |
| Dihydroxyphenazine | A-256, A-257, A-260 | Antibacterial and anti-Trypanosoma brucei (Dashti et al., 2014) |
| Dinactin | A-266, A-271 | Antibiotic (Silva et al., 2014); cytokine production inhibitor (Umland et al., 1999) |
| E 492 | A-50 | Anti-inflammatory (Ma et al., 2018) |
| E 975 | A-50 | Anti-inflammatory (Ma et al., 2018) |
| Echinomycin | A-250 | Antitumor, antimicrobial (Kim et al., 2004) |
| Endophenazine D | A-256 | Antibiotic (Gebhardt et al., 2002) |
| Feigrisolide C | A-266, A-271 | Antiviral, antibacterial (Tang et al., 2000), antifungal against Plasmopara viticola zoospores (Islam et al., 2016) |
| Feigrisolide D | A-266, A-271 | Antibacterial (Tang et al., 2000) |
| Ferrioxamine E | A-169 | Siderophore (Berner et al., 1988) |
| Fumaramidmycin/N-[1-Hydroxy-2-(1H-indol-3-yl)-2-oxoethyl]acetamide* | A-50 | Antibacterial (Maruyama et al., 1975) |
| Furanones | A-241 | Antibiotic and antibiofilm (de Nys et al., 2006) |
| Geldanamycin | A-120 | Antifungal, anticancer, neurotrophic and neuroprotective (Tadtong et al., 2007) |
| Germicidin A | A-53 | Spore germination, hypha elongation (Aoki et al., 2011) |
| Germicidin D | A-50 | Spore germination, hypha elongation (Aoki et al., 2011) |
| Glycerol 2-(15-methylhexadecanoate)/ Aggreceride C* | A-262 | Platelet aggregation inhibitor (Omura et al., 1986) |
| Homononactic acid | A-271 | Insecticidal (Jizba et al., 2008) |
| Ikarugamycin epoxide | A-249 | Antibiotic against Gram-positive bacteria and fungi, strongly cytotoxic (Bertasso et al., 2003) |
| Ilamycin A/C1/C2 | A-159 | Cytotoxic (Ma et al., 2017) |
| Ilamycin B1 | A-159, A-261 | Unknown |
| JBIR 07/JBIR 08/N-Nonanoylhomoserine lactone/N-(7-Methyloctanoyl)homoserine lactone* | A-261 | Autoinducer, signaling molecule (Patel et al., 2016) |
| Kahakamide A | A-256 | Antimicrobial (Schumacher et al., 2001) |
| Lansai D | A-263 | Anti-inflammatory (Taechowisan et al., 2010) |
| Lipoamide C | A-261 | Antimicrobial (Berrue et al., 2009) |
| Lyngbic acid | A-268 | Unknown |
| Maniwamycin A | A-171 | Antifungal (Nakayama et al., 1989) |
| N-(2-hydroxyphenyl)acetamide | A-257 | Immunosupressant (Jawed et al., 2010) |
| Pentaminomycin D | A-87 | Autophagy inducer (Hwang et al., 2020) |
| Pentaminomycin E | A-87 | Unknown |
| Methylsulfomycin I | A-105 | Antibiotic (Vijaya Kumar et al., 1999) |
| Monactin | A-266, A-271 | Antibiotic (Jizba et al., 1991) |
| N-Acetyl-4-hydroxybenzylamine/N-(2-Methoxyphenyl)acetamide/N-Methylphenylacetohydroxamic acid* | A-69 | Unknown |
| N-Acetylisoleucine | A-265 | Unknown |
| N-Acetyl-N-methyl-D-fucosamine | A-261 | Unknown |
| N-Acetyltyramine | A-266 | Antitumor human melanoma and leukemia (Kanou et al., 1998), Antifungal (Garcez et al., 2000), radical scavenging (Heidari and Mohammadipanah, 2018) |
| Narbosine B | A-171 | Antiviral (Henkel et al., 1991) |
| Naseseazine A | A-87 | Unknown |
| Naseseazine B | A-87 | Antiplasmodial (Gomes et al., 2019 |
| N-Butanoylhomoserine lactone | A-171, A-249 | Quorum-sensing signal molecule in Gram-negative bacteria (Chan et al., 2011) |
| N-N-Dimethyladenosine | A-268 | Inhibitor of AKT signaling in lung cancer cell lines (Vaden et al., 2017) |
| Non-actic acid | A-266, A-271 | Antibiotic and antitumor (Meyers et al., 1965) |
| Non-actins | A-178, A-266, A-271 | Ammonium ionophore, antibacterial, antiviral, antitumor (Zhan and Zheng, 2016) |
| O1,O2,O3,O4,N-Penta-Ac Valiolamine | A-139 | Unknown |
| Ostreogrycin B | A-258 | Antibiotic (Cocito, 1979) |
| Piperafizine B | A-169, A-256 | Cytotoxicity potentiator (Kamei et al., 1990) |
| Prodigiosins | A-241 | Antifungal, antimalarial, antitumor, immunosuppressive (Williamson et al., 2006; Stankovic et al., 2014; Darshan and Manonmani, 2015) |
| Questiomycin A/Crystalloiodinine B/1,8-Dihydroxyphenazine/1,9-Dihydroxyphenazine/2,3-Dihydroxyphenazine/1-Hydroxyphenazine 10-oxide* | A-169 | Antibacterial (Shimizu et al., 2004), anticancer (Che et al., 2011) |
| Ravidomycin | A-254 | Antibiotic, antitumor (Sehgal et al., 1983) |
| Respinomycin D | A-178 | Antibiotic, antitumor (Ubukata et al., 1993) |
| Salaceyin A | A-254 | Cytotoxic (Kim et al., 2006), antifungal (Park et al., 2007) |
| Salaceyin B | A-254 | Cytotoxic (Kim et al., 2006), antifungal (Park et al., 2007) |
| Terferol (5′-Methoxy-[1,1′:4′,1′′-terphenyl]-2′,3′-diol)/3′-Methoxy-[1,1′:4′,1′′-terphenyl]-2′,6′-diol/3′-Methoxy-[1,1′:4′,1′′-terphenyl]-2′,5′-diol* | A-53 | Unknown |
| Tetrahydro-5-methyl-6-(1-methylbutyl)-3-(2-methylpropyl)-2H-pyran-2-one/13-Methyl-4-tetradecenoic acid/12-Methyl-4-tetradecenoic acid* | A-258 | Unknown |
| Tetranactin | A-266, A-271 | Antibiotic, immunosuppressive and anti-proliferative (Tanouchi and Shichi, 1988) |
| Tetronomycin | A-254 | Antibiotic (Keller-Juslén et al., 1982) |
| Tirandamycin A | A-171 | Antiamoebic (Espinosa et al., 2012), antibiotic (Meyer, 1971) |
| Tirandamycin B | A-171 | Antibiotic (Meyer, 1971) |
| Trinactin | A-266, A-271 | Antibiotic, immunosuppressive (Tanouchi and Shichi, 1987) |
| Violapyrone F | A-241 | Unknown |
| Virginiamycin M1 | A-258 | Antibiotic (Cocito, 1979) |
| Undecylprodigiosin | A-241 | Antibiotic, cytotoxic (Petrović et al., 2017), immunosuppressor (Songia et al., 1997; Williamson et al., 2006) |
| Virginiamycin M2 | A-258 | Antibiotic (Cocito, 1979) |
| Xenocyloin C | A-261 | Antibiotic (Paul et al., 1981), insecticidal (Proschak et al., 2014) |
| XR 330 | A-43, A-256 | Inhibitor of plasminogen activator inhibitor-1 activity (Bryans et al., 1996) |
| XR 334 | A-169 | Inhibitor of plasminogen activator inhibitor-1 activity (Bryans et al., 1996) |
| α,5-Dimethyl-2-oxo-4-imidazolidinehexanoic acid | A-171 | Unknown |
| α-Methyldethiobiotin | A-50 | Antibiotic (Hanka et al., 1972) |
Identified compounds produced by atmospheric derived Actinobacteria strains and their biological activities.
The asterisk means that more than one compound was identified. The highlightened strains correspond to Nocardiopsis species, the rest are Streptomyces species. A: A-43, A-53, A-69, A-139, A-167, A-169, A-249, A-250, A-254, A-256, A-257, A-258, A-260, A-261, A-262, A-263, A-265, A-266, A-268, A-269, A-271. B: A-69, A-249, A-250, A-254, A-258, A268. C: A-241, A-250, A-254, A-258, A-269.
Of great interest, 30 compounds had molecular formulae determined by HRMS not reported for any molecule included inNatural Products Databases(Supplementary Material 2). These molecules, 28 produced by Streptomyces species and two by Nocardiopsis sp. A-169, deserve further research since they might be new natural products and thus candidates for the discovery of new biologically active substances. Table 5 shows the number of identified compounds, the number of novel molecules produced by each strain, and the results of meteorological analyses to estimate the sources and trajectories of the different air masses that caused the precipitation events, estimated with a 5-day NOAA Hysplit Model (Figure 3). Concerning novel molecules, 20 were produced by strains isolated in the Northern Spain sampling places and 10 by strains isolated in Southern Spain. The air masses of the Southern precipitation event (strains A-258, A-261, A-262, A-266) originate in the Atlantic Ocean. The air masses corresponding to the Northern Spain precipitation events were also sourced in the Atlantic Ocean (strains A-167, A-169, A-249, and A-171), but in some cases (strains A-53, A-254, A-269, A-271) they originate in the Arctic Ocean, and continental America, strain A-87 in United States and strain A-139 in Canada.
TABLE 5
| Strain | Number of products | Sampling place | Sampling date | Air masses backward trajectories analysesa | |
| Unidentified | Identified | ||||
| Nocardiopsis sp. A-43 | 5 | Gijón | 04/11/2013 | California, United States South states from West to the East, Labrador (Canada), Atlantic Ocean. | |
| Streptomyces sp. A-50 | 8 | Gijón | 19/12/2013 | Northwest Passage (Artic Ocean), Atlantic Ocean, Spain | |
| Streptomyces sp. A-53 | 2 | 3 | Gijón | 19/12/2013 | Northwest Passage (Artic Ocean), Atlantic Ocean, Spain |
| Streptomyces sp. A-69 | 7 | Gijón | 15/12/2014 | Pacific Ocean, Oregon, United States (from West to East), Terranova, Atlantic Ocean. | |
| Streptomyces sp. A-87 | 1 | 6 | Gijón | 15/12/2014 | Louisiana, Missisipi, Alabama, Georgia, South Carolina (United States), Atlantic Ocean, Labrador Terranova (Canada), Atlantic Ocean, Greenland, United Kingdom, France, Cantabrian Sea |
| Streptomyces sp. A-139 | 4 | 3 | Gijón | 18/01/2015 | Manitoba, Ontario, Quebec, Terranova, Labrador (Canada), Atlantic Ocean, Arctic Ocean Iceland, Portugal, Spain |
| Streptomyces sp. A-167 | 2 | 3 | Gijón | 15/09/2015 | Atlantic Ocean, Portugal, Spain |
| Nocardiopsis sp. A-169 | 2 | 9 | Gijón | 15/09/2015 | Atlantic Ocean, Portugal, Spain |
| Streptomyces sp. A-171 | 1 | 8 | Gijón | 5/10/2015 | Atlantic Ocean, Portugal, Mediterranean Sea |
| Streptomyces sp. A-178 | 4 | Gijón | 3/1/2016 | Arctic Ocean (Baffin Bay), Hudson Bay, Quebec (Canada), Arctic Ocean, Atlantic Ocean, Portugal, Spain | |
| Streptomyces sp. A-179 | 1 | Gijón | 5/1/2016 | Pacific Ocean, Alaska (United States), North East Canada, Atlantic Ocean | |
| Streptomyces sp. A-241 | 6 | Gijón | 27/02/2016 | Michigan, New York, Maine (United States), Quebec (Canada), Atlantic Ocean | |
| Streptomyces sp. A-249 | 1 | 11 | Oviedo | 13/09/2016 | Atlantic Ocean, Portugal, Spain |
| Streptomyces sp. A-250 | 11 | Oviedo | 13/09/2016 | Atlantic Ocean, Portugal, Spain | |
| Streptomyces sp. A-254 | 3 | 9 | Oviedo | 15/09/2016 | Arctic Ocean, Atlantic Ocean, Cantabrian Sea |
| Nocardiopsis sp. A-256 | 10 | Seville | 13/09/2016 | Atlantic Ocean, Spain | |
| Nocardiopsis sp. A-257 | 6 | Seville | 13/09/2016 | Atlantic Ocean, Spain | |
| Streptomyces sp. A-258 | 3 | 10 | Seville | 13/09/2016 | Atlantic Ocean, Spain |
| Nocardiopsis sp. A-260 | 7 | Seville | 13/09/2016 | Atlantic Ocean, Spain | |
| Streptomyces sp. A-261 | 4 | 9 | Seville | 13/09/2016 | Atlantic Ocean, Spain |
| Streptomyces sp. A-262 | 2 | 13 | Seville | 13/09/2016 | Atlantic Ocean, Spain |
| Streptomyces sp.A-263 | 6 | Seville | 13/09/2016 | Atlantic Ocean, Spain | |
| Streptomyces sp. A-265 | 4 | Seville | 13/09/2016 | Atlantic Ocean, Spain | |
| Streptomyces sp. A-266 | 1 | 12 | Seville | 13/09/2016 | Atlantic Ocean, Spain |
| Streptomyces sp. A-268 | 11 | Oviedo | 13/09/2016 | Atlantic Ocean, Portugal, North Spain | |
| Streptomyces sp. A-269 | 2 | 7 | Oviedo | 15/09/2016 | Arctic Ocean, Atlantic Ocean, Cantabrian Sea |
| Streptomyces sp. A-271 | 2 | 11 | Oviedo | 15/09/2016 | Arctic Ocean, Atlantic Ocean, Cantabrian Sea |
Number of compounds and sources of the producing Actinobacteria strains isolated from rainwater precipitations.
aSummary of the backward trajectories estimated with a 5-day NOAA Hyspli Model as shown in Figure 3.
Discussion
Exploration of the diversity of Actinobacteria producing biologically active natural products in the atmosphere was herein addressed by sampling multiple precipitation events with prevalent Westerly winds over 4 years in different sampling sites in Spain. Most of the isolates obtained from rainwater samples tolerate high salt concentrations and are homologs of known species isolated from very diverse terrestrial and marine ecosystems throughout the planet, in places as deep as the Mariana Trench sediments (10,898 m depth) in the Pacific Ocean, and as high as the Himalaya Mountains (8,849 m) (Table 2). Taxonomic identification and phylogenetic analyses of the atmospheric-derived Actinobacteria reported here, revealed Streptomyces as the most dominant genus, thus increasing the number of cultivable Streptomyces species able to survive and disperse via the atmosphere. Bioactive members of the rare actinobacterial genus Nocardiopsis were also isolated homologous to two species, Nocardiopsis alba and Nocardiopsis synnemataformans. The global number of Nocardiopsis species described so far on Earth is estimated in 50–53.2
The most relevant feature of the atmospheric Actinobacteria strains studied is that they are producers of multiple chemically diverse secondary metabolites, as analyzed by LC-UV-MS. Ten of the strains produced more than ten compounds each, up to a maximum of 15 (Table 5). From a total of 169 compounds detected after LC/MS dereplication, 82.25% were identified in the Dictionary of Natural Products, whereas, remarkably, the remaining 17.75%, not found in DPN, might be new molecules and deserve further research. After a literature search, 55% of the identified compounds were found to be biologically active as antibiotics (both against Gram-positive and Gram- negative bacteria and against fungi) and 23% have antitumor or cytotoxic activities; compounds with antiparasitic, anti-inflammatory, immunosuppressive, antiviral, insecticidal, neuroprotective, antiarthritic and other diverse biological activities were also detected in the extracts. The number of the compounds produced by these strains is estimated to be much higher than the one presented here, since only diffusible apolar molecules produced in a single culture conditions were analyzed, and possible diffusible polar or volatile molecules were not studied.
Meteorological analyses of the air masses involving 5 days HYSPLIT backward trajectories indicate a main oceanic source from the North Atlantic Ocean and also terrestrial sources from continental North America and Western Europe. In some events even long-range transport from the Pacific and the Arctic Oceans were also estimated. These bacteria remain viable after their atmospheric transport by winds across oceans and continents at planetary level. They could travel downwind and be dispersed via the atmosphere during long periods of time before they fall down to earth by precipitation. These findings provide further support for the Streptomyces atmospheric dispersal cycle (Sarmiento-Vizcaíno et al., 2016), which is herein extended to other members of the phylum Actinobacteria, such as Nocardiopsis genus.
The Streptomyces species herein identified are different from the ones previously isolated in a North-western wind precipitation event, sampled in North Spain and sourced in West Greenland and North Iceland and Canada (Sarmiento-Vizcaíno et al., 2018), thus indicating the relevance of winds in Streptomyces biogeographical distribution. Also, different Nocardiopsis species were isolated in different sampling places, which approximately differ in 6 latitudinal degrees, 37° N in South Spain to 43° N in North Spain sampling place. Latitude has been shown to delineate Streptomyces biogeography patterns in North America terrestrial environments (Choudoir et al., 2016).
Our findings make evident that across time, during different precipitation events, and space, by changing the latitude of the sampling place, we can have access to a striking diversity of Actinobacteria producing an extraordinary reservoir of bioactive natural products from remote and very distant origins, thus highlighting the relevance of the atmosphere as a here and now stablished source for the discovery of novel compounds of relevance in medicine and biotechnology.
Conclusion
Results here obtained on Actinobacteria isolated in rainwater from storm clouds transported by Western winds in Spain highlights the relevance of the atmosphere as a main source of diverse Streptomyces and Nocardiopsis species, and increases our knowledge of the biogeography of these Actinobacteria genera on Earth. Our findings included also an amazing reservoir of bioactive molecules produced by these Actinobacteria, and take another step forward on the potential of atmospheric precipitations for the discovery of natural products active as antibiotic and antitumor agents, among others.
Publisher’s Note
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Statements
Data availability statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.
Author contributions
AS-V and GB isolated the strains. AS-V performed the bioactivity assays, taxonomic identification, and phylogenetic analyses of the strains, and extraction of compounds produced, and analyzed the compounds by LC-UV. GB analyzed the air masses backward trajectories. JM and FR performed the metabolite profiling analysis and identified the compounds produced by LC-MS. LG and GB conceived and coordinated the project. GB wrote the manuscript which has been revised and approved by all authors.
Funding
This study was financially supported by the Universidad de Oviedo (Ayuda PAPI-18-PUENTE-6).
Acknowledgments
We are grateful to José L. Martínez and Daniel Serna (Servicios científico-técnicos, edificio Severo Ochoa, Universidad de Oviedo) for their help in strains identification, and Julia Espadas for providing the Seville sample. This is a contribution of the Asturias Marine Observatory.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmicb.2021.773095/full#supplementary-material
Supplementary Material 1UV210 nm chromatograms corresponding to all samples.
Supplementary Material 2Compounds whose molecular formulae was not found in the Dictionary of natural products.
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Summary
Keywords
Streptomyces, Nocardiopsis, actinomycetes, antibiotic, antimicrobial, antitumor
Citation
Sarmiento-Vizcaíno A, Martín J, Reyes F, García LA and Blanco G (2021) Bioactive Natural Products in Actinobacteria Isolated in Rainwater From Storm Clouds Transported by Western Winds in Spain. Front. Microbiol. 12:773095. doi: 10.3389/fmicb.2021.773095
Received
09 September 2021
Accepted
14 October 2021
Published
10 November 2021
Volume
12 - 2021
Edited by
Pierre Amato, UMR 6296 Institut de Chimie de Clermont-Ferrand (ICCF), France
Reviewed by
Loh Teng Hern Tan, Monash University Malaysia, Malaysia; Maria King, Texas A&M University, United States
Updates
Copyright
© 2021 Sarmiento-Vizcaíno, Martín, Reyes, García and Blanco.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Gloria Blanco, gbb@uniovi.es
This article was submitted to Extreme Microbiology, a section of the journal Frontiers in Microbiology
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