**1. Introduction**

Antibiotics, the so-called "miracle drugs," came into existence half a century ago; however, their current popularity swiftly leads to overuse. Over the last decade, it has become quite apparent that the efficiency of antibiotics is dropping due to the growth of pathogen resistance; a problem that increases as fewer new drugs become available in the market. Moreover, unraveling this resistance is not straightforward, since antibiotic resistance is actually produced in multiple ways. Considering the urgency of the issue, efforts to develop new antibiotics are being carried out by pharmaceutical companies. In this regard, natural products account for a thorough and important component of today's pharmaceutical compendium as a fundamental source of chemical diversity. To date, several natural products have been studied, but many others still await investigation [1]. Cyanobacteria, being one of the eldest

recognized creatures living on the earth with exclusive structural features, produce several bioactive compounds with varied biological activities. Moreover, cyanobacteria as photosynthetic microorganisms, which have been preserving the oxygen levels on the earth, structurally look like gram-negative bacteria. They include chlorophyll *a* and phycobiliproteins, as well as the photosystems II and I. The adaptation mechanisms shown by cyanobacteria allow them to survive in severe climate conditions and tolerate limiting factors, such as heat, drought, salinity, nitrogen starvation, cold, photo-oxidation, osmotic, and UV stress [2]. Additionally, cyanobacteria are able to produce biologically active natural products with known antifungal, antibacterial, anti-inflammatory, antiviral, and enzyme-inhibiting bioactivities mostly through either the nonribosomal polypeptide (NRP) or the mixed polyketide-NRP biosynthetic pathways [3]. An increasing number of cyanobacterial metabolites are found to target actin and tubulin filaments in eukaryotic cells, making them a noteworthy source of anticancer natural products. Definite bioactive compounds, for example, dolastatin-10 and curacin A, have gone through clinical trials as possible anticancer drugs [4]. Cyanobacterial bioactive products can be categorized consistently with diverse structural typologies comprising terpenes, polyketides, peptides, lipids, and alkaloids. Many structural modifications can be found in cyanobacterial compounds, especially polyketide-derived units [3]. Besides, each cyanobacterial strain produces a category of bioactive compounds, so that new drugs are being constantly discovered from these sources.

Along with all these advantageous features, cyanobacteria are also known to produce toxins, mainly neurotoxins and hepatotoxins [2, 5], which act also as activators (e.g., antillatoxin) or blockers (e.g., jamaicamide A and kalkitoxin) and in addition their possible neuroprotectant and analgesics properties, they are functional molecular to distinguish usefully channels [4, 6–8].

Patellamide and trunkamide have also clinical potential, showing moderate cytotoxicity but multi-drug resistance. Investigations about the cyanobacterial natural product and secondary metabolites have gradually adapted to the genomic revolution over the past 15 years, and the genetic characterization of these secondary metabolites has led to further investigations in the field of cyanobacterial natural product synthesis. Despite important achievements in this area, numerous pharmaceutical companies have decreased the use of natural bioactive products and drug discovery screening because of: a) difficulties associated with strain, b) troubles correlated to natural bioactive products, and c) problems with logical property rights [9–14]. Finally, the use of compound collections prepared by combinatorial chemistry methods has been also influential.

### **2. Improving access to natural products**

It is now evident that the chemical diversity of natural products is a better option than the variety of available synthetic compounds for drug discovery [15, 16]. Therefore, the use of natural chemical diversity in this regard is becoming increasingly frequent [11, 17]. Early publications showed that only a small number of cyanobacteria taxa were accessible for screening [9]. Now, extensive cyanobacteria collections, together with better cyanobacteria culture techniques, are providing new chemicals for use in drug discovery assays [11]. Progress is being made in the chemistry of natural products, leading to advances in synthetic methods seeking the production of compound analogs with enhanced pharmacological or pharmaceutical

#### *Cyanobacteria Natural Products as Sources for Future Directions in* Antibiotic *Drug Discovery DOI: http://dx.doi.org/10.5772/intechopen.106364*

characteristics [18]. Another interesting feature that has made natural product "privileged" structures is their ability to be used as cores of compound (alkaloids, polyketides, terpenoids, and flavonoids) libraries produced through combinatorial techniques [19, 20].

Over the past 30 years, there has been a considerable reduction in the interest by the leading pharmaceutical companies in drug discovery from natural sources. Despite this, phycologists, associated with the manufacturing industry, are exploiting this niche so that there is now a renaissance related to new improvements in spectroscopy, analytical technologies, and high-throughput screening [21]. In addition, competing technologies, such as combinatorial chemistry, have not proved to be very successful in delivering the new drug in significant numbers [22]. With the use of alternative techniques to produce analogs and derivatives of natural products, new compounds can be patented, even if the primary structure had been previously disclosed [11].

### **3. New approaches to the value of natural products**

Multitude reasons have been suggested in regards to why natural products are such appropriate sources for drug leads, but at least one study has endeavored to quantify a connection between the drug molecules and those typically found in natural products and combinatorial chemical libraries [22]. Combinatorial libraries are synthesized in large numbers, and structures have high randomness. A multivariate evaluation of the chemical space occupied by thousands of combinatorial drug compounds compared with that of natural products revealed a good correlation between clinically approved drug molecules with natural products. This means that the structure of drugs used nowadays can be simulated by that of natural products [15]. With the progress in analytical spectroscopy, numerous clarifications are currently accessible so that the discovery of new bioactive compounds needs only a few micrograms [22]. The improvement in fractionation methods intended for isolating and purifying natural bioactive products (counter-current chromatography [20], analytical structure determination [23], etc. has led to screening natural product mixtures with timescales suitable for those expected in high-throughput screening campaigns. Complex structures can be resolved now with much less than 1 mg of the compound using the recent NMR techniques [11]. According to Quinn (developing a drug-like natural product library, 2008), it is possible to prepare a screening a library of highly diverse plant-derived compounds by pre-selecting products from the dictionary of natural products to be drug-like in their physicochemical properties. Yet, many alternative approaches are also being tested in order to enhance the speed and efficiency of drug discovery from natural products [11]. For instance, bioinformatics has been used for predicting microbes, which are able to produce new chemicals on the basis of the gene sequences encoding polyketide synthesis; this method has led to the discovery of potential antifungal and anticancer activities in some compounds [24]. Furthermore, the Metagenomics approach, which has led to the discovery of antibiotic compounds, has been recently used to achieve a broader range of synthetic cyanobacterial capabilities. This involves the collection of the entire DNA from a field cyanobacteria sample and the cloning of this DNA in host organisms, such as E. coli. Recombinant bacteria are subsequently cultured and examined for the expression of bioactive metabolites [11]. Additionally, peptide synthetase genes and polyketide synthase genes have been explored, and manipulation of biosynthetic pathways in refractory microbes, such as

uncultivable, is a promising line of research. Along with the most innovative tools of genetic engineering, new approaches to metagenomic mining of environmental DNA are being popularized, so that the genetic potential of many bacteria can be explored [25]. Even though more than 200 genome projects are either already completed or still undergoing publication, there are still some striking questions on what is actually being sequenced, considering the fact that these studies are limited to cultivable microbes. The Metagenomics approach, being culture-independent, can help to solve this problem and can also help with data mining with potential interest for a broad scientific community [25]. Different techniques unite enzymatic and synthetic methods to achieve multifaceted natural bioactive products, and refining the activity of obviously occurring antibiotics [11]. Mutasynthetic techniques are useful for making the antibiotic daptomycin-associated compounds [26, 27], vancomycin analogs and anticancer compound cryptophicin have been formed using the cytochrome P450 enzymes [12]. The biosynthesis of cyanobacterial compounds supports the creation of numerous functional groups, chiefly in the gene clusters related to cyanobacterial compounds, for instance, jamaicamide A, barbamide, or curacin A [28]. Hence, undescribed enzymatic mechanisms will be revealed thanks to biochemical studies in cyanobacterial secondary metabolic pathways. From the experience in the production of pharmaceuticals from invertebrate-derived microbes, it is evident that several obstacles must be overcome before this approach becomes a conventional technology. Still, there are good reasons to be optimistic about the future [22].
