Tedania Ignis Classification Essay

2. Macrocyclic Drugs

Although the structural complexity and synthetic intractability limit their pharmaceutical application, macrocycles have broad applications in drug discovery and development; and numerous natural macrocyclic compounds present exceptional therapeutic potential and unrivalled biological activities [1]. Historically, macrocyclic molecules represent a successfully documented drug class in the clinic. In this section we review clinically used macrocyclic drugs and mainly focus on their structural aspect, mechanism of action and primary clinical indication. Notably, the macrocyclic antibiotics (Figure 1 , Figure 2) constitute one of the most successful classes of macrocyclic drugs in clinical practice. Among them, vancomycin is a macrocyclic glycopeptide antibiotics for the treatment of Gram-positive bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumonia [9,10]. Chemically, vancomycin is a hydrophilic glycopeptide containing a glycosylated hexapeptide chain and aromatic rings cross linked by aryl ether bonds into a rigid molecular framework. It is not orally bioavailable due to poor absorption in the gastrointestinal tract, however, it can be used as an oral antibiotic for the treatment of C. difficile-associated diarrhea and enterocolitis caused by Staphylococcus aureus [9,10]. In 2009, its synthetic lipoglycopeptide derivative telavancin was approved by the U.S. FDA for the treatment of complicated skin and skin structure infections (cSSSIs) caused by MSSA, MRSA, and vancomycin-susceptible Enterococcus faecalis, and Streptococcus pyogenes, Streptococcus agalactiae, or Streptococcus anginosus group [10,11,12]. Mechanistically, this glycopeptide class inhibits the peptidoglycan biosynthesis of bacterial cell wall by binding tightly to D-alanyl-D-alanine portion of cell wall precursor, as well as disrupts cell membrane integrity [10,13,14].

Figure 1. Clinically used macrocyclic antibiotics.

Figure 1. Clinically used macrocyclic antibiotics.

Figure 2. Additional macrocyclic antibiotics.

Figure 2. Additional macrocyclic antibiotics.

In addition, daptomycin is a new cyclic lipopeptide antibiotic produced from Streptomyces roseosporus [15]. It was approved by the U.S. FDA in 2003 for the treatment of cSSSIs caused by susceptible aerobic Gram-positive organisms and S. aureus bacteremia caused by MSSA or MRSA [10,16]. Daptomycin rapidly depolarizes bacterial membrane by binding to components of the cell membrane of susceptible organisms and inhibits macromolecular biosynthesis of DNA, RNA, and protein [10,17]. Fidaxomicin, obtained from the fermentation broth of Dactylosporangium aurantiacum subspecies hamdenesis, represents the first in a new macrocyclic class of narrow spectrum antibiotics [18,19,20]. It was approved by the U.S. FDA for the treatment of C. difficile-associated diarrhea in 2011 [10]. Bacitracin A, generated from the licheniformis group of Bacillus subtilis, is a branched cyclic polypeptide broad spectrum antibiotic targeting both Gram-positive and -negative organisms [21,22]. It works by inhibiting the late stage peptidoglycan biosynthesis and disrupting plasma membrane function [23]. Polymyxins A-E belong to an old class of cationic cyclic polypeptide antibiotics that consist of a cyclic positively charged decapeptide with an either 6-methyl-octanic acid or 6-methyleptanoic acid fatty acid side chain. Only polymyxins B and E in this class are used in the clinic, which are primarily used for the treatment of Gram-negative bacterial infections such as Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species [10,24,25,26]. Polymyxin B disrupts bacterial membrane integrity by binding to phospholipids in cytoplasmic membranes [10,25].

The prototype macrolide antibiotic erythromycin, bearing a 14-membered macrocyclic lactone motif, was isolated from the fermentation broth of the fungus Saccharopolyspora erythraea and used for the treatment of susceptible bacterial infections [27,28]. Clarithromycin, a semisynthetic derivative of erythromycin with a 6-methoxyl ether functionality and improved acidic stability, is an effective macrolide antibiotic for the treatment of chronic bronchitis and erysipelas [29,30]. Azithromycin, a 15-membered expanded ring derivative of erythromycin, is another advanced and effective antibacterial agent in this macrolide class [29,30]. Telithromycin, the first ketolide antibiotic bearing a 14-membered lactone ring and an interesting alkyl-aryl side chain linked with a cyclic carbamate moiety, was approved by the U.S. FDA in 2004 and is used for the treatment of mild-to-moderate community-acquired pneumonia [10,30,31]. This class of macrolide antibiotics exerts its antibacterial action by binding to the 50S subunit of the bacterial ribosome resulting in the inhibition of RNA-dependent protein synthesis [10,32]. Spiramycin is another glycomacrolide antibiotic which is currently not available in the U.S.. It inhibits bacterial growth of susceptible organisms with unknown mechanism of action; and is used for the treatment of bacterial infections of the respiratory tract, buccal cavity, skin and soft tissues due to susceptible organisms [10,33].

As shown in Figure 2, the streptogramin family represents another important class of naturally occurring macrocyclic antibiotics, which includes streptogramin A, streptogramin B, quinupristin, and dalfopristin [34]. This chemical class functions as bacterial protein synthesis inhibitors [34]. Structurally, the streptogramin group A has a 23-membered unsaturated macrolactone with peptide bonds, while the streptogramin group B belongs to a cyclic hexadepsipeptide class. The combination of quinupristin and dalfopristin is used synergistically for the treatment of cSSSIs caused by MSSA or Streptococcus pyogenes [10,35].

Rifamycin and its derivatives constitute another notable class of antibacterial agents. The rifamycin antibiotic family includes rifampin, rifapentine, rifabutin, and rifaximin. Chemically, this class consists of a 25-membered macrolactam ring bearing a naphthalenic aromatic moiety connected to an aliphatic chain. Mechanistically, this antibacterial class inhibits bacterial RNA synthesis by binding to the β-subunit of DNA-dependent RNA polymerase [36] and it is primarily used for the treatment of tuberculosis except that rifaximin is clinically used for the treatment of traveler’s diarrhea caused by noninvasive strains of E. coli [10]. In addition, capreomycin (administered as a mixture of capreomycin 1A and 1B) is a strongly basic and cyclic polypeptide antibiotic, which is used in the second line TB regimens for the treatment of multi-drug resistant tuberculosis (MDR-TB) in conjunction with other antibiotics [10,37].

Macrocyclic antifungal agents are illustrated in Figure 3. Nystatin, amphotericin B, and natamycin belong to a chemical class of polyene antifungal drugs, which structurally consists of a macrocyclic lactone scaffold; a hydrophilic region containing multiple OH groups, a COOH functionality, and an aminosugar moiety; and a hydrophobic region containing a chromophore of the 4–7 conjugated double bond system. This naturally occurring antifungal class works by binding to ergosterol in fungal cell membrane and thus disrupting fungal membrane function [38,39]. Nystatin, the first clinically used agent in this polyene class, displays potent activity for invasive Candida infection; however, it can only be used topically due to its severe toxicity for systemic use [10]. In contrast, amphotericin B is used parenterally for the treatment of severe systemic and CNS fungal infections caused by susceptible fungi [10]. Natamycin is the only topical ophthalmic antifungal agent approved by the U.S. FDA for the treatment of blepharitis, conjunctivitis, and keratitis caused by susceptible fungi (Aspergillus, Candida, Cephalosporium, Fusarium, and Penicillium) [10].

Figure 3. Clinically used macrocyclic antifungal and antiparasitic agents.

Figure 3. Clinically used macrocyclic antifungal and antiparasitic agents.

Structurally, antifungal echinocandins belong to a lipopeptide chemical class, which includes a large cyclic hexapeptide linked to a long fatty acid tail or lipophilic side chain. The echinocandin family includes anidulafungin, caspofungin, and micafungin and is used parenterally for the treatment of candidemia, other forms of Candida infections, and invasive Aspergillus infections [10,40,41,42]. This drug class demonstrates antifungal activity by inhibiting 1,3-β-D-glucan synthase, an important target in the fungal cell wall biosynthesis [39,40].

On the other hand, macrocycles have also been used as antiparasitic agents. One such example, ivermectin, bearing a 16-membered macrocyclic ring, is an effective antiparasitic and anthelmintic agent for the treatment of strongyloidiasis of the intestinal tract and onchocerciasis, as well as the topical treatment of head lice (Figure 3) [10,43,44]. Ivermectin binds to glutamate-gated chloride ion channels with high selectivity and strong affinity in invertebrate nerve and muscle cells, which ultimately leads to the death of the parasite due to increased permeability of cell membranes to chloride ions and subsequent hyperpolarization of the nerve or muscle cell [10,43].

Macrocyclic anticancer chemotherapeutic agents are shown in Figure 4. As one of the older chemotherapy drugs, dactinomycin, isolated from soil bacteria of the genus Streptomyces, is a cyclic polypeptide intravenous antibiotic with anticancer activity [45]. It binds to DNA and causes subsequent inhibition of RNA synthesis and is used in the treatment of Wilm’s tumor, gestational trophoblastic neoplasia and rhabdomyosarcoma [10]. Epothilone B, a 16-membered polyketide macrolactone with a methylthiazole side chain, exerts its cytotoxic effects through promoting microtubule assembly, interfering with the late G2 mitotic phase, and inhibiting cell replication [10]. It has similar mechanistic profile as taxanes but improved solubility and milder side effect and become a new class of anticancer drugs for the treatment of metastatic or locally-advanced breast cancer (refractory or resistant) [10,46]. The semisynthetic macrolactam analogue ixabepilone of epothilone B is used for the treatment of advanced breast cancer [47]. In addition, romidepsin, a histone deacetylase (HDAC) inhibitor generated from the bacteria Chromobacterium violaceum, is an antineoplastic prodrug for the treatment of refractory cutaneous T-cell lymphoma and refractory peripheral T-cell lymphoma [10,48].

Figure 4. Macrocycles used as cancer chemotherapeutic and immunosuppressant agents.

Figure 4. Macrocycles used as cancer chemotherapeutic and immunosuppressant agents.

Macrocycles have also been clinically used as immunosuppressant agents, one such example, the cyclic polypeptide cyclosporine inhibits the production and release of interleukin-2 (IL-2), inhibits IL-2-induced activation of resting T-lymphocytes and thus inhibits T cell-mediated immune responses [10,49]. It is frequently used to prevent rejection in organ transplant recipients [10]. Another macrolide lactone class of immunosuppressive agents includes sirolimus (rapamycin) [50

Geographic Range

The range of Tedania ignis, common name fire sponge, is primarily in the Neotropical Region; however, there are significant populations in the southern Neartic Region. The southernmost population exists off the coast of Brazil and extend as far north as South Carolina. There have been reports of T. ignis in the Southern Pacific near Hawaii however these are unconfirmed and could be attributed to the difficulty of classifying species within the family Tedaniidae. (Wulff, 2006)

Habitat

Fire sponges are found in shallow tropical waters with a relatively slow but steady water flow. They usually live at depths between 0.5-2 m. Tedania ignis are found in two general habitats: amongst red mangrove roots and in coral reefs. When in association with a reef habitat T. ignis generally hides in cryptic locations under patches of coral rubble due to the increase in predation by fish. (Engel and Pawlik, 2005; Maldonado and Young, 1996; Pawlik, 1998)

Physical Description

In general fire sponges are conspicuous with a bright orange color. They are sessile, growing in low mounds extending in all directions, approximately 1 cm thick. Oscula are scattered throughout the organism. The shape and size of spicules are a major characteristic used for classification and identification of sponges. The spicules of T. ignus are smooth with curved styles and the tylotes are straight with microspined ends. Tedania ignus has spicules ranging in size from 50-270 µm in length and 32.-9.8 µm in width. The diameter of the ostial openings are 3.5-14.0 µm. (Simpson, 1984; Wulff, 2006)

Tedania ignus can be difficult to differentiate from other species in the same family. One example of this is Tedania klausi which shares the bright orange coloring with T. ignus. Both species have similar spicule sizes. However, they can be differentiated by the more defined volcano shaped columns with a single osculum in Tedania klausi. (Dunlap and Pawlik, 1996; Wulff, 2006)

Development

Often within the class Demospongiae, sponges brood embryos and eventually release parenchymella larvae. The larvae of T. ignus have a flagella tuft which it uses to swim while finding a suitable space for settlement. Larvae can respond to light to a certain extent to guide their search but that their eventual settlement is largely attributed to the water currents and conditions. Once the larvae find a suitable substrate location they will settle and metamorphose into adults. This transformation and growth period involves four basic stages: the formation of functional areas including, choanocyte chambers, mesohyl, pinacoderms, ostia and the initial stages of oscules; maturation of functional tissues, increasing complexity of skeletal structure and canal system; remodeling of mature tissue; and the general increase in size. The growth rate of a sponge is largely dependent on the environmental conditions, specifically light, food and space. ("Demosponge", 2002; Maldonado and Young, 1996; Simpson, 1984)

Reproduction

While T. ignus does not display specific mating behavior, most species in the class Demospongiae are capable of both asexual and sexual reproduction. The method of reproduction varies on environmental factors such as physical or biological disturbances. Furthermore, sponges are incredibly adept at regeneration. (Simpson, 1984; Tanaka-Ichihara and Wantanabe, 1985)

Sponges, Tedania ignus included, do not have true reproductive organs. However, there are multiple ways sponges use to reproduce including, larval metamorphosis, differentiation of tissue, production of gemmules and budding. In asexual reproduction the gemmules are an aggregation of mesohyl cells. Typically 8 to 12 eggs are in each brooded group at the beginning of the reproductive period. The production of gemmules is seasonal and varies among species. In T. ignus larvae release occurs from late April through August. Larvae are released through the ectosome which is the dermal layer. (Battershill and Bergquist, 1985; Maldonado and Young, 1996; Simpson, 1984)

Tedania ignus does not have any parental care; once the gametes are released the sessile parent has no further role. (Battershill and Bergquist, 1985)

Lifespan/Longevity

The lifespan of an individual organism is difficult to quantify because of the regeneration and asexual reproduction. (Simpson, 1984)

Behavior

Tedania ignus responds to various experimental stimuli through a reaction in the oscules. For example, a reduction in hydrostatic pressure caused partial oscular closure. Fire sponges were not affected by electric stimuli or by slight changes in pH of the surrounding water. Finally, stretching the oscule for short periods resulted in contraction; however, it did not contract if stretched for longer periods of time. ("Demosponge", 2002; Simpson, 1984)

Tedania ignus is a sessile organism in the adult stage. In the larval stage T. ignus is flagellar and can swim to an appropriate location for settlement. However, the swimming abilities are rather limited and often the settlement site is determined by water currents and turbulence in the area. In similar sponge species larvae can swim several millimeters per second. Tedania ignus is known for its ability to successfully over grow other sponge species when competing for space. (Engel and Pawlik, 2005; Maldonado and Young, 1996; Warburton, 1996)

Communication and Perception

As in all Porifera, fire sponges lack a nervous system and therefore have little ability to communicate or perceive the outside environment. However there is evidence that larvae have the ability to respond to light as an indicator for determining the final location of settlement. While not confirmed one theory is that the posterior flagelar tuft which provides locomotor capabilities may contain pigment granules used for photoresponse. (Maldonado and Young, 1996)

Food Habits

Tedania ignus is a filter feeder consuming small and large planktonic particles. One study found the specific filtration rate of T. ignus to be 1597 milliliters per hour per gram of tissue. It also had significantly higher filtration rates when fed a mix of different phytoplankton. (Pererson, et al., 2006)

Predation

Sponges have adapted a variety of predatory defenses including, tough fibrous components, noxious chemical substances and mineralized sclercites. Diketopiperazines were previously ascribed to T. ignus but these chemicals were found to be produced by a bacterium thought to be a Microccus species. Studies have also found inactive or mildly cytotoxic components which may have tumor-inhibitory characteristics. As a cryptic sponge living in either mangrove patches or under coral rubble fire sponges have weaker defenses than conspicuous reef sponges and are favored by predators. There are several specialized fish and non-fish predators that have specialized to overcome the defenses of T. ignus. (Dunlap and Pawlik, 1996; Muller, 2003; Pawlik, et al., 1995; Schmitz, et al., 1983; Wulff, 2006)

Ecosystem Roles

Tedania ignus is a facultative mutualist with red mangroves, by both providing the plant with a source of nitrogen and protecting the roots from root boring isopods. Tedania ignus profits by having a physically stable and conspicuous habitat. Furthermore, fire sponges have been found to play an important role in the conservation of biological diversity. A decrease in biomass of T. ignus and other suspension feeders in combination with an increase in nitrogen and phosphorous pollution have resulted in devastating phytoplankton and cyano bacteria blooms in the Florida Bay area. These blooms have led to the deterioration of the ecosystem and loss of biodiversity in the estuary. In addition marine sponges as a whole serve a crucial role to the overall reef system by stabilizing physically damaged reefs, nutrient cycling, providing a food source and acting as primary producers. (Bell, 2008; Engel and Pawlik, 2005; Pererson, et al., 2006)

Commensal/Parasitic Species

Economic Importance for Humans: Positive

Unlike other sponge species T. ignus is not a directly commercial itself. Instead, it helps control phytoplankton blooms which can be detrimental to the overall ecosystem and have a negative impact on commercially relevant species. T. ignus, along with other sponges are being investigated for potential pharmacological uses from the bioactive compounds with antiviral and antibacterial characteristics. ("Demosponge", 2002; Pererson, et al., 2006)

  • research and education
  • controls pest population

Economic Importance for Humans: Negative

There are no data on the number of people that suffer from contact dermatitis as a result of an encounter with T. ignus but it may be a health hazard. (Schmitz, et al., 1983)

Conservation Status

Tedania ignus is not listed by the International Union for Conservation of Nature (ICUN), The United States Federal list of endangered species, or by CITES species database. This is likely due to a lack of research that has been conducted on the size of populations. (Pererson, et al., 2006)

Contributors

Mary McCarthy (author), University of Michigan-Ann Arbor, Phil Myers (editor), University of Michigan-Ann Arbor, Renee Mulcrone (editor), Special Projects.

References

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Bell, J. 2008. The functional roles of marine sponges. Estuarine, Costal and Shelf Science, 79: 341-353.

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