**6.2. Drug discovery from soil microorganisms**

Soil microorganisms (Figure 3), such as bacteria and fungi, play central roles in soil fertility and promotion of plant health. It is assessed that in 1 g of soil there are 4000 different bacte‐ rial ''genomic units'' based on culture independent identification methods. In the other hand, an estimated 1,500,000 species of fungi, but they are more difficult to cultivated by standard methods [14].

In soil there is a constant exchange of organic substances and flow of energy. Feeding, pre‐ dation, degradation of macromolecular substrates and absorption of nutrients have been im‐ portant in chemical processes in soil. One of the most important microorganism in drug discovery found in natural habitat mainly in soil are the actinomycetes which are very di‐ verse family of bacteria, they are an important source of bioactive compounds with high val‐ ue in pharmaceutical industry. It's have been reported that almost 80% of the world`s antibiotics come from the genera *Micromonospora* and *Streptomyces.* Beside this, the majority of the actinomycetes in soil that are potential drug sources remain uncultivable, and there‐ fore in cannot be screened for novel antibiotic discovery [5].

Has been reported that microorganisms found in soil are a plentiful source of chemically di‐ verse bioactive compounds, and have been an important source for the discovery of antibac‐ terial agents including penicillins, cephalosporins, aminoglycosides, tetracyclines, and polyketides [2].

Also, from 117 actinomycetes strains isolated from the wasteland alkaline and garden soil samples in India, were found 15 actinomycetes strain that showed antimicrobial activity against at least two pathogen bacteria between them *Staphylococcus aureus*[5].

According to reference [15], environmental factors, such as carbon and energy sources, mineral nutrients, growth factors, ionic composition, available water, temperature, pressure, air compo‐ sition, electromagnetic radiation, pH, oxidation–reduction potential, surfaces, spatial relation‐ ships, genetics of the microorganisms and interaction between microorganisms, can alter the microbial diversity, activity and population dynamics of microorganisms in soil. It is important to mention that almost 80–90% of the microorganisms habiting soil are on solid surfaces [15].

**Figure 3.** Bacteria strains from soil samples in Valle de las Palmas, Mexico.

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**Figure 3.** Bacteria strains from soil samples in Valle de las Palmas, Mexico.

Several studies reported a great variety of microorganism present in air samples, for exam‐ ple, a study realized in Mexico, in 2007, showed 21 species of bacteria founded in air sam‐ ples from landfill, some of them are pathogenic and opportunistic bacteria, the most abundant are *Pasteurella haemolytica, Serratia plymuthica*, *Escherichia coli* y *Klebsiella pneumonia* and 19 fungal species, 7 of them allergenic, *Cladosporium herbarum, Aspergillus* sp y *Penicilli‐ um* sp. [10]. Despite this, *Serratia plymuthica*it's well known to possess 2-amino-3-(oxir‐ ane-2,3-dicarboxamido)-propanoyl-valine has been shown to inhibit the growth of the

Another studies found airborne microbes collected at indoor air with filters installed in two shopping centers in Singapore. The most common microorganism appears to be several spe‐ cies of *Brevundimonas* (50%) [12] other study has identified *Brevundimonas diminuta*as pro‐ ducer of a nematicidal metabolite known as (R)-(-)-2-ethykhexan-1-ol which have a strong

Soil microorganisms (Figure 3), such as bacteria and fungi, play central roles in soil fertility and promotion of plant health. It is assessed that in 1 g of soil there are 4000 different bacte‐ rial ''genomic units'' based on culture independent identification methods. In the other hand, an estimated 1,500,000 species of fungi, but they are more difficult to cultivated by

In soil there is a constant exchange of organic substances and flow of energy. Feeding, pre‐ dation, degradation of macromolecular substrates and absorption of nutrients have been im‐ portant in chemical processes in soil. One of the most important microorganism in drug discovery found in natural habitat mainly in soil are the actinomycetes which are very di‐ verse family of bacteria, they are an important source of bioactive compounds with high val‐ ue in pharmaceutical industry. It's have been reported that almost 80% of the world`s antibiotics come from the genera *Micromonospora* and *Streptomyces.* Beside this, the majority of the actinomycetes in soil that are potential drug sources remain uncultivable, and there‐

Has been reported that microorganisms found in soil are a plentiful source of chemically di‐ verse bioactive compounds, and have been an important source for the discovery of antibac‐ terial agents including penicillins, cephalosporins, aminoglycosides, tetracyclines, and

Also, from 117 actinomycetes strains isolated from the wasteland alkaline and garden soil samples in India, were found 15 actinomycetes strain that showed antimicrobial activity

According to reference [15], environmental factors, such as carbon and energy sources, mineral nutrients, growth factors, ionic composition, available water, temperature, pressure, air compo‐ sition, electromagnetic radiation, pH, oxidation–reduction potential, surfaces, spatial relation‐ ships, genetics of the microorganisms and interaction between microorganisms, can alter the microbial diversity, activity and population dynamics of microorganisms in soil. It is important to mention that almost 80–90% of the microorganisms habiting soil are on solid surfaces [15].

against at least two pathogen bacteria between them *Staphylococcus aureus*[5].

human pathogen *Candida albicans* efficiently [11].

activity against *C. elegans* and *B. xylophilus* [13].

**6.2. Drug discovery from soil microorganisms**

fore in cannot be screened for novel antibiotic discovery [5].

standard methods [14].

314 Drug Discovery

polyketides [2].

#### **6.3. Drug discovery from water microorganisms**

The world's oceans comprise about 70 % of the earth's surface, where the extensive drug discovery efforts involving soil bacteria have not been extended to this ecosystem [16]. This environment have special attention since is known that typical microbial abundance of 106 per ml in the water column and 109 per ml in ocean bottom sediments. Actinobacteria is among the most dominant population and successful phyla of all environments [17]. This class takes into account 5 subclasses, 9 orders, 55 families, 240 genera and 3000 species [18].

others. Recently, one study in the Gulf of California [32] found Operational Taxonomic Units (OTUs) belonging *Streptomyces* and *Actinomadura* genus and a potentially represent a new genus-level taxon in the family *Streptomycetaceae*. In addition, several previously descri‐ bed marine species were isolated including *Micromonospora krabiensis, Saccharomonospora marina, Streptomyces fenhuangensis, Verrucosispora maris* and *Verrucosispora sediminis* suggest‐

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The genes involved in secondary metabolism are responsible for the biosynthesis of small molecules that mediate important functional traits such as allelopathy, chemical communi‐ cation and iron acquisition [33]. These compounds have been used to assess biogeographical

Polyketide synthase (PKSI) genes are called Type I and are responsible for the production of many important secondary metabolites including the antibiotic erythromycin [35] and the

Bacteria can maintain complex assemblies of PKS genes [37], many of which are not ex‐ pressed under normal laboratory conditions [38]. Recently, a study found that HGT plays an important role in the evolution of PKSI genes and that ketosynthase (KS) domains within polyketide synthase genes are phylogenetically important making predictions about pro‐ duction of secondary metabolites by complex biosynthetic pathways [39-40]. Other method used for providing further evidence for endemism associated with secondary metabolites [33], is the terminal restriction fragment length polymorphism (T-RFLP) used to demon‐

According to [32] targeting KS domains provides a rapid method to assess PKS diversity and novelty within individual strains. The results revealed evidence of common pathways shared with other *Salinispora* strains but also sequences that share low levels of identity with any characterized pathways and thus may be associated with the production of new secon‐ dary metabolites. It is noteworthy that the new sequence type "L" also possesses a KS se‐

Secondary metabolites are linked to an organism's fitness and therefore represent an emerg‐ ing marker to study population structure and function, taxonomically meaningful patterns of secondary metabolite production have been detected in bacteria [42] and fungi [43].

Progress has also been made in drug discovery from actinomycetes by using high through‐ put screening and fermentation, metabolic profiling technologies, genome scanning, mining genomes for cryptic pathways, and combinatorial biosynthesis to generate new secondary metabolites related to existing pharmacophores [17, 44]. Metagenomic screening of DNA from environmental samples [45-46] provides an alternative way of discovering new antibi‐

According to [47] recently published new web tools that provide automated methods to assess the secondary metabolite gene diversity; those are the Natural Product Domain Seeker (NaP‐ DoS) analysis based on the phylogenetic relationships of sequence tags derived from polyketide synthase and non-ribosomal peptide synthethase (NRPS) genes. These results are compared

strate that subpopulations of bacteria cluster together based on collection site [41].

quence that has not previously been observed in "*S. pacifica".*

ing that these species may have broad geographic distributions.

patterns among bacteria [34].

otic biosynthetic genes.

anticancer agent epothilone [35-36].

From all actinobacteria, Marine Actinobacteria have become the most important source of secondary metabolites with medical application, such as anticancer, antibiotics, antitumor, anti-inflammatory, and antifungal compounds [16-17, 19].

Actinobacteria, called commonly actinomycetes are Gram positive bacteria having a higher guanine plus cytosine (G+C) percentage in its DNA than any other bacteria. Most of these organisms are aerobic (oxidative), some are facultative or forced anaerobes (fermentation) [20]. These microorganisms grow as networks called mycelium. They structures are filamen‐ tous. Sometimes are on the surface, for that is called aerial mycelium, or substrate mycelium if it attaches to the substrate surface [21]. The individual filaments of the mycelium or hy‐ phae are divided into units as a result of growth of the cell wall into the hyphae at regular intervals along this structure. This process is called septation and each of the resulting septa contains one DNA molecule. The mycelium bacterium is analogous to the mycelium form‐ ing filamentous fungi [22]. Actinobacteria produce spores in specialized hyphae many of which are developed on the aerial filament, sometimes these spores are flagellated. The Acti‐ nobacteria inhabit the soil where play an important role in soil chemistry, the characteristic odor of soil is due to special metabolites that are known as Geominas [23]. Actinobacteria also inhabit aquatic environments including those marine. Actinomycetes are the most eco‐ nomically and biotechnologically valuable prokaryotes [24].

Almost 60 years in actinomycetes researches, more than 15000 bioactive compounds have been discovery for academic and pharmaceutical researchers many of which are used as drugs today. Fact more than half of the antibiotics discovered to date are obtained from the soil-derived actinomycete bacteria *Streptomyces* and *Micromonospora* genus spores [25].

The majority of the actinomycetes isolated from marine sources was largely of terrestrial ori‐ gin and had been washed to shore and existed in the ocean as metabolically inactive spores [25]. Recently, phylogenetic analyses of the 16S rRNA genes indicate that existing new taxa widely distributed in ocean sediments [26], including some that appear to be unique and ob‐ ligate marine actinomycete bacteria [27]. These strains represent the most significant source of naturally occurring microbial antibiotics [17, 28- 30] and antitumor compounds [28- 30] with specific metabolic and physiological capabilities that had not been observed in terres‐ trial microorganisms before [31-32]. Members of this group are producers of clinically useful antitumor drugs such as anthracyclines, glycopeptides,aureolic acids, enediynes, antimeta‐ bolites, carzinophilin, mitomycins and others [19].

The studies related with new biodiversity and drugs discovery had been examined from waters all around the world such as San Diego Bay, Bahamas, Fiji and Guam Islands among others. Recently, one study in the Gulf of California [32] found Operational Taxonomic Units (OTUs) belonging *Streptomyces* and *Actinomadura* genus and a potentially represent a new genus-level taxon in the family *Streptomycetaceae*. In addition, several previously descri‐ bed marine species were isolated including *Micromonospora krabiensis, Saccharomonospora marina, Streptomyces fenhuangensis, Verrucosispora maris* and *Verrucosispora sediminis* suggest‐ ing that these species may have broad geographic distributions.

**6.3. Drug discovery from water microorganisms**

anti-inflammatory, and antifungal compounds [16-17, 19].

nomically and biotechnologically valuable prokaryotes [24].

bolites, carzinophilin, mitomycins and others [19].

per ml in the water column and 109

316 Drug Discovery

The world's oceans comprise about 70 % of the earth's surface, where the extensive drug discovery efforts involving soil bacteria have not been extended to this ecosystem [16]. This environment have special attention since is known that typical microbial abundance of 106

among the most dominant population and successful phyla of all environments [17]. This class takes into account 5 subclasses, 9 orders, 55 families, 240 genera and 3000 species [18]. From all actinobacteria, Marine Actinobacteria have become the most important source of secondary metabolites with medical application, such as anticancer, antibiotics, antitumor,

Actinobacteria, called commonly actinomycetes are Gram positive bacteria having a higher guanine plus cytosine (G+C) percentage in its DNA than any other bacteria. Most of these organisms are aerobic (oxidative), some are facultative or forced anaerobes (fermentation) [20]. These microorganisms grow as networks called mycelium. They structures are filamen‐ tous. Sometimes are on the surface, for that is called aerial mycelium, or substrate mycelium if it attaches to the substrate surface [21]. The individual filaments of the mycelium or hy‐ phae are divided into units as a result of growth of the cell wall into the hyphae at regular intervals along this structure. This process is called septation and each of the resulting septa contains one DNA molecule. The mycelium bacterium is analogous to the mycelium form‐ ing filamentous fungi [22]. Actinobacteria produce spores in specialized hyphae many of which are developed on the aerial filament, sometimes these spores are flagellated. The Acti‐ nobacteria inhabit the soil where play an important role in soil chemistry, the characteristic odor of soil is due to special metabolites that are known as Geominas [23]. Actinobacteria also inhabit aquatic environments including those marine. Actinomycetes are the most eco‐

Almost 60 years in actinomycetes researches, more than 15000 bioactive compounds have been discovery for academic and pharmaceutical researchers many of which are used as drugs today. Fact more than half of the antibiotics discovered to date are obtained from the soil-derived actinomycete bacteria *Streptomyces* and *Micromonospora* genus spores [25].

The majority of the actinomycetes isolated from marine sources was largely of terrestrial ori‐ gin and had been washed to shore and existed in the ocean as metabolically inactive spores [25]. Recently, phylogenetic analyses of the 16S rRNA genes indicate that existing new taxa widely distributed in ocean sediments [26], including some that appear to be unique and ob‐ ligate marine actinomycete bacteria [27]. These strains represent the most significant source of naturally occurring microbial antibiotics [17, 28- 30] and antitumor compounds [28- 30] with specific metabolic and physiological capabilities that had not been observed in terres‐ trial microorganisms before [31-32]. Members of this group are producers of clinically useful antitumor drugs such as anthracyclines, glycopeptides,aureolic acids, enediynes, antimeta‐

The studies related with new biodiversity and drugs discovery had been examined from waters all around the world such as San Diego Bay, Bahamas, Fiji and Guam Islands among

per ml in ocean bottom sediments. Actinobacteria is

The genes involved in secondary metabolism are responsible for the biosynthesis of small molecules that mediate important functional traits such as allelopathy, chemical communi‐ cation and iron acquisition [33]. These compounds have been used to assess biogeographical patterns among bacteria [34].

Polyketide synthase (PKSI) genes are called Type I and are responsible for the production of many important secondary metabolites including the antibiotic erythromycin [35] and the anticancer agent epothilone [35-36].

Bacteria can maintain complex assemblies of PKS genes [37], many of which are not ex‐ pressed under normal laboratory conditions [38]. Recently, a study found that HGT plays an important role in the evolution of PKSI genes and that ketosynthase (KS) domains within polyketide synthase genes are phylogenetically important making predictions about pro‐ duction of secondary metabolites by complex biosynthetic pathways [39-40]. Other method used for providing further evidence for endemism associated with secondary metabolites [33], is the terminal restriction fragment length polymorphism (T-RFLP) used to demon‐ strate that subpopulations of bacteria cluster together based on collection site [41].

According to [32] targeting KS domains provides a rapid method to assess PKS diversity and novelty within individual strains. The results revealed evidence of common pathways shared with other *Salinispora* strains but also sequences that share low levels of identity with any characterized pathways and thus may be associated with the production of new secon‐ dary metabolites. It is noteworthy that the new sequence type "L" also possesses a KS se‐ quence that has not previously been observed in "*S. pacifica".*

Secondary metabolites are linked to an organism's fitness and therefore represent an emerg‐ ing marker to study population structure and function, taxonomically meaningful patterns of secondary metabolite production have been detected in bacteria [42] and fungi [43].

Progress has also been made in drug discovery from actinomycetes by using high through‐ put screening and fermentation, metabolic profiling technologies, genome scanning, mining genomes for cryptic pathways, and combinatorial biosynthesis to generate new secondary metabolites related to existing pharmacophores [17, 44]. Metagenomic screening of DNA from environmental samples [45-46] provides an alternative way of discovering new antibi‐ otic biosynthetic genes.

According to [47] recently published new web tools that provide automated methods to assess the secondary metabolite gene diversity; those are the Natural Product Domain Seeker (NaP‐ DoS) analysis based on the phylogenetic relationships of sequence tags derived from polyketide synthase and non-ribosomal peptide synthethase (NRPS) genes. These results are compared with an internal experimentally database. NaPDoS provides a rapid mechanism used to infer the generalized structures of secondary metabolites biosynthetic gene richness and diversity within a genome or environmental sample by extract and classification of ketosynthase and con‐ densation domains from PCR products, genomes, and metagenomic datasets increasing expo‐ nentially the investigations in this field of science with benefits in the field of drug discovery.

**7. Conclusion**

their competitors [4].

formulation.

**Author details**

na, BC., México

na, BC., México

Graciela Lizeth Perez-Gonzalez3

Bioactive compounds isolated from aerial, terrestrial and marine organisms have extensive past and present use in the treatment of many diseases and serve as compounds of interest both in their natural form and as templates for synthetic modification. To found new com‐ pounds useful to develop new pharmaceutical drugs, a good potential source and diverse bioactive chemicals is microorganism present in natural sources as air, soil and water.

Chemical compounds from natural sources are the major protagonists in chemical diversity for pharmaceutical discovery over the past century. The interesting chemicals identified as natural products are derived from the biodiversity in which the interactions between micro‐ bial entities and their environment formulate the diverse complex chemical entities within the organisms that enhance their survival and competitiveness. Hence, it is important to study inter and intraspecific interactions between microorganism in natural environments,

Microbial interactions can influence the secretion of bioactive compound. Has been report‐ ed, various types of contacts among bacterial species and other organism. For example, these relations can be negative (parasitism, competition and predation) or positive (metabio‐ sis and symbiosis) for these microorganisms. Between interactions in microorganism we can emphasize competition. Some bacteria are reduced by different species when the environ‐ mental resources are limited; therefore they produce compounds that impress negatively in

Finally, air, soil and water are the home of microorganism that compete all the time to sur‐ vive, resist changes in temperature, pressure, nutrient, carbon and nitrogen content, micro‐ organisms that are obligated to produce weapons against predators, change and mutate to scape of detection of other microbes. All this, are the reason why we can find an unimagina‐ ble number and variety of chemical that are effective to be part of a pharmaceutical drug

1 Center of Engineering and Technology, University Autonomous of Baja California, Tijua‐

2 Marine Science Faculty, University Autonomous of Baja California, Ensenada, BC., México

3 Center of Engineering and Technology, University Autonomous of Baja California, Tijua‐

, Ana Leticia Iglesias3

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and

this will make the screening for bioactive compounds in microbes easier.

Luis Jesús Villarreal-Gómez1\*, Irma Esthela Soria-Mercado2

\*Address all correspondence to: luis.villarreal@uabc.edu.mx

Table 1 shows a list of microorganisms isolated from different sources which produce anti‐ oxidant, antibacterial, anticoagulant, antiviral, anti-inflammatory, immune system, antidia‐ betic and nematicidal activities, as well as their action mechanisms.


**Table 1.** Microorganism isolated from natural sources that produce bioactive compounds
