**Abstract**

Ascidians belonging to Phylum Chordata are the most largest and diverse of the Sub-phylum Tunicata (Urochordata). Marine ascidians are one of the richest sources of bioactive peptides. These bioactive peptides from marine ascidians are confined to various types of structures such as cyclic peptides, acyclic peptides (depsipeptides), linear helical peptides with abundance of one amino acid (proline, trytophane, histidine), peptides forming hairpin like beta sheets or α-helical/β-sheet mixed structures stabilized by intra molecular disulfide bonding. Cyanobactins are fabricated through the proteolytic cleavage and cyclization of precursor peptides coupled with further posttranslational modifications such as hydroxylation, glycosylation, heterocyclization, oxidation, or prenylation of amino acids. Ascidians are known to be a rich source of bioactive alkaloids. β-carbolines form a large group of tryptophan derived antibiotics. Pyridoacridines from ascidians are tetra- or penta- cyclic aromatic alkaloids with broad range of bioactivities. Didemnidines derived from ascidian symbiotic microbes are inhibitors of phospholipase A2 and induce cell apoptosis. Meridianins are indulged in inhibiting various protein kinases such as, cyclindependent kinases, glycogen synthase kinase-3, cyclic nucleotide dependent kinases, casein kinase, and also implicate their activity of interfering with topoisomerase, altering the mitochondrial membrane potential and binding to the DNA minor groove to inhibit transcriptional activation. Most of these bioactive compounds from ascidians are already in different phases of the clinical and pre-clinical trials. They can be used for their nutraceutical values because of their antineoplastic, antihypertensive, antioxidant, antimicrobial, cytotoxic, antibacterial, antifungal, insecticidal, anti-HIV and anti-parasitic, anti-malarial, anti-trypanosomal, anti-cancer etc. This chapter mostly deals with antibacterial compounds from ascidian and their associate symbiotic cyanobacteria.

**Keywords:** Ascidians, Chordata, depsipeptides, β-carbolines, pyridoacridines

## **1. Introduction**

Ascidians commonly known as tunicates or sea squirts are soft bodied and sessile animals belonging to subphylum urochordates. Sac like sea squirt ascidians produce many toxic nitrogen bearing secondary metabolites that are implicated in their chemical defense [1]. Ascidians belonging to family *Didemnidae, Prochloron* species symbiotic bacteria produce a variety of toxic and cyclic peptides known

as cyanobactins [2]. Ascidians of this family have yielded structurally unique and pharmacological compounds such as didemnenones, enterocins, paterallazoles, varacins and virenamides [3]. Didemnin, isolated at first from the Caribbean tunicate *Trididemnin solidum*. Didemnin B capable of antiproliferative activity against human cancer cell lines. Didemnin B inhibits the synthesis of RNA, DNA and proteins [4]. It is found that Didemnin B being the first natural marine derived peptide to be evaluated in clinical trials, because of its dose-dependent and tolerable toxicity profiles. Toxicity profile of Didemnin B with dose dependent nausea and vomiting are the most commonly mentioned side effects [4]. However at the higher doses, Didemnin B causes severe cardiotoxicity.

Aplidine is a cyclodepsipeptide has sufficient activity against a variety of human cancer cell lines such as breast, melanoma and lung cancers [5]. Aplidine has several functional activities such as Inhibition of protein synthesis, cell cycle arrest, induction of apoptosis on cancer cells and inhibition of vascular endothelial growth factor gene. Its actions on causing cytotoxicity, involves the inhibition of ornithine decarboxylase, an enzyme that is responsible for the tumor formation and tumor growth [6]. Its approval on Phase-I clinical trial, induces on its minor toxicity tolerance limit with most of its side effects corresponding to asthenia, nausea, vomiting and transient transaminitis etc. [7].

Mollamides being a cyclodepsipeptide has suitable cytotoxic activity against a wide range of cancer cell lines such as human lung carcinoma and human colon carcinoma [8].

Trunkamide A, a cyclodepsipeptide with a thiazoline ring similar to mollamide, show antitumor activity under preclinical trials [9]. This peptide contains the thiazoline-based proline on doubly prenylated cyclopeptides. Heterocyclic amino acids such as the tryptophan and histidine also forms the part of proline rich cyclic peptides structures such as wainunuamide, phakellistatin 15,17 and stylissatin B.

However, recently pharmaceutical industries are gaining more insights on antimicrobial peptides due to their increased efficacy, high specificity, low toxicity, decreased drug interaction and direct attacking properties.

## **2. Alkaloids**

Alkaloids are providing the majority of ascidian originating bioactive compounds. They represent a highly diverse group of compounds containing cyclic structures having a basic nitrogen atom incorporated within it. Ascidians on the other hand are produces of large quantity of alkaloids and modified peptides which exhibit a wide range of biological properties such as, Cytotoxicity, antibiotic, immunosuppressive activities, inhibition of topoisomerases (TOPO), cyclin kinase, display antimicrobial and anticancer activities by inhibiting kinase activity, including protein kinase B (PKB), Cyclin dependent kinases (CDKs), altering mitochondrial membrane potential and binding to the DNA minor groove to inhibit transcriptional activation [10].

Investigations on the biosynthesis of secondary metabolites provide evidence on the *de-novo* biosynthesis by ascidians [11]. Ascidians are a source of nitrogen bearing secondary metabolites with a varied range of biological activities. Many biological active compounds have been isolated from ascidians, it is still unclear whether this animal or associated microbial symbionts such as bacterial or fungi are true sources for the synthesis of biosynthetic metabolites.

A specific biosynthetic source of the alkaloids such as, granulatimide and isogranulatimides by specifically localizing these compounds lying inside ascidians. *Antimicrobial Peptides Derived from Ascidians and Associated Cyanobacteria DOI: http://dx.doi.org/10.5772/intechopen.99183*

Granulatimide stored in *Didemnum granulatum* tunic bladder cells were analyzed by confocal fluorescence microscopy at the granulatimide emission range, indicated the presence of fluorescent cells as highly vacuolated cells found to be dispersed in ascidian tunic [12]. Thus, this is the most exposed ascidian tissue, it pertains to show that this alkaloids may have a protective role.

#### **2.1 Didemnidines**

Didemnidines A and B are two indole spermidine alkaloids isolated from ascidian Didemnum species. Didemnidines A and B are both active as inhibitors of phospholipase A2, farnesyltransferase enzyme without cytotoxicity. It has moderate cytotoxicity towards malarial parasite, L6 cells and inhibition parasite proliferation. Antiparasitic activity of didemnidine B provides the opportunity to explore the didemnidines as antimalarial and antitrypanosomal agents [13].

#### **2.2 Meridianins**

Meridianins are brominated 3-(2-aminopyrimidine)-indoles isolated from the ascidian *Aplidium meridianum* [14]. As these meridianins are structurally similar to variolins, meridianins are identified as a promising kinase inhibitory scaffolds, which inhibits various protein kinases such as, Cyclin dependent kinases, glycogen synthase kinase 3, cyclin nucleotide dependent kinases and casein kinase [15].

#### **2.3 Herdmanines**

Herdmanines represent a series of nucleoside derivatives isolated from the ascidian *Herdmania monus*. Herdmanines A to D inhibit the production and the expression of messanger RNA, Pro-inflammatory cytokines, while herdmanines C and D are found to have moderate suppressive effects on the pro-inflammatory cytokines and lipopolysaccharides (LPS) induced nitricoxide [16].

#### **2.4 Ecteinascidins**

This peptide belonging to tetrahydroisoquinoline alkaloid family exhibits potent antitumor activity. It binds with the major groove of DNA and leads to the sequence specific alterations in transcription, triggers DNA cleavage, causing double stranded break, interruption of the cell cycle, apoptosis of cancer cell and down regulation of some transcriptional [17] factors.

#### **2.5 Eusynstyelamides**

Eusynstyelaides, alkaloids isolated from ascidian *Eusynstye latatericus*. It has specific cytotoxic activity against neuronal nitric oxide synthase (nNOS), anticancer and antibacterial activities. Eusynstyelaides B, a secondary metabolite from a bryozoan species, suggested that these components could be synthesized by symbiotic microbes. Eusynstyelaides B exhibits anti-proliferative activity and causes a strong cell cycle block and also induces cell apoptosis [18]. Eusynstyelamides A–C show specific cytotoxicity against neuronal nitric oxide synthase (nNOS) and show anticancer and antibacterial activity [19]. Eusynstyelamides A and B display, inhibitory activities against *Staphylococcus aureus*, plant regulatory enzymes pyruvate phosphate dikinase (PPDK) [20].

#### **2.6 Sesbanimide**

Sesbanimide A, peptide isolated from Agrobacterium. Sesbanimide C showed activity against the growth of mouse leukemia cells and inhibited the proliferation of mouth epidermal carcinoma (kb) cell [21]. It was evaluated against various human cancer cell lines.

#### **2.7 Mollamide**

A cyclodepsipeptide isolated from the ascidian *Didemnum molle*, shows specific cytotoxic activity towards a range of cell lines with IC 50 values of 1ug/ml towards P388murine leukemia cell lines and 2.5ug/ml resistance towards A549 human lung carcinoma and HT29 human colon carcinoma [22]. Neuromuscular toxicity with the elevation of creatine phosphatase levels has been dose limited, but seemed to be readily irreversible with oral carnitine. Aplidine has shown antitumor activity in phase-I clinical trials and in phase-II clinical trials in solid tumors.
