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Antimicrobial lead compounds from marine plants

Marine environment is a home to a very wide diversity of flora and fauna, which includes an array of genetically diverse coastline and under seawater plant species, animal species, microbial species, their habitats, ecosystems, and supporting ecological processes. The Earth is home to an estimated 10 million species, of which a large chunk belongs to marine environment. Marine plants are a store house of a variety of antimicrobial compounds like classes of marine flavonoids—flavones and flavonols, terpenoids, alkaloids, peptides, carbohydrates, fatty acids, polyketides, polysaccharides, phenolic compounds, and steroids. Lot of research today is directed toward marine species, which have proved to be a potent source of structurally widely diverse and yet highly bioactive secondary metabolites. Varied species of phylum Porifera, algae including diatoms, Chlorophyta, Euglenophyta, Dinoflagellata, Chrysophyta, cyanobacteria, Rhodophyta, and Phaeophyta, bacteria, fungi, and weeds have been exploited by mankind for their inherent indigenous biological antimicrobial compounds, produced under the extreme stressful underwater conditions of temperature, atmospheric pressure, light, and nutrition. The present study aims at presenting a brief review of bioactive marine compounds possessing antimicrobial potency.


Flavonoids (Bioflavonoids)
Flavones and flavonols (flavusdLatin for yellow) are present in plant and fungi as secondary metabolites and are naturally yellow in color. Chemical structure has a 15-carbon skeleton, with two phenyl rings (A and B) and one heterocyclic ring (C); abbreviated as C6eC3eC6. They are anthoxanthins (flavones and flavonols), ketone-containing polyhydroxy polyphenol compounds. More than 5000 natural flavonoids are studied from flora and fauna, classified according to their chemical structure. Flavonoids have been shown to have a wide range of biological and pharmacological activities such as antibacterial [4], antiviral, antifungal [5], antimicrobial, antidiarrheal activities [6], antiinflammatory [7], and antioxidant [8]. Flavonoids show antibacterial potency, synergism with antibiotics along with suppression of virulence factors in bacteria [9].

Terpenoids/Isoprenoids/modified terpenes
Terpenoids are organic chemicals derived from terpenes, which can also be termed as modified terpenes, in which either methyl groups are removed or transferred or oxygen atoms are added. Simple terpenoids and unusual terpenoids are found in ample amount in flora growing in marine environment. Isopentenyl pyrophosphate and dimethylallyl pyrophosphate condense to produce geranyl pyrophosphate, which is a precursor to all terpenes and terpenoids.
Cytochrome P450s modify the structure of terpenes and this property is found to be due to enzymes terpenoid synthase encoded by genes of 17 plant species genomes [10]. Sesterterpenoids, sesquiterpenoids, and meroterpenoids found to be antimicrobial and antiviral are more commonly found in marine environments. Marine sesterterpenoids exhibiting prominent antimicrobial and antiviral bioactivities occur in marine sponges [11]. Seven different types of sesterterpenes sulfates were isolated from tropical sponge belonging to Dysidea sp., of which most were found strong isocitrate lyase inhibitors showing potent antibacterial effect against Bacillus subtilis and Proteus vulgaris [12]. Hyrtiosal is a bioactive sesterterpenoid isolated from Hyrtios erectus, which is a marine sponge inhibiting HIV integrase (IN), which binds to viral DNA at a new binding site for inhibitor, observed to bind to HIV N-terminal domain at Ser17, Trp19, and Lys34, having potential application in anti-HIV research [13]. Terpenes possess 1,4-benzoquinone supposed to be responsible for antimicrobial and antiviral properties. Puupehanol, a novel sesquiterpene-dihydroquinone derivative, and chloropuupehenone and puupehenone are responsible for antifungal activity in marine sponge Hyrtios sp. extract [14]. Puupehenone proved most inhibitory against Candida krusei and Cryptococcus neoformans. Nakijiquinones G-I from Okinawan marine sponges, belonging to family Spongilidae, were found to be a sesquiterpenoid quinone with antimicrobial potency [15]. Novel sesquiterpenoid hydroquinones from Dysidea arenaria, a marine sponge, were found moderately inhibitory for enzyme HIV reverse transcriptase (RT) [16]. Peyssonoic acids A and B, novel sesquiterpene hydroquinones, with a novel carbon skeleton, isolated from crustose marine red alga Peyssonnelia sp [17] were found inhibitory for bacterial pathogen Pseudoalteromonas bacteriolytica in marine algae and Lindra thalassiae, a fungal pathogen of marine algae.

Alkaloids
Alkaloids are a vast group of heterogenous natural nitrogenous metabolites, thickly interwoven with human affairs. Morphine takes the credit of being the first alkaloid, isolated from opium poppy Papaver somniferum, in 1804, by Friedrich Sertürner, a German chemist [24]. Alkaloids are bitter, natural, organic compounds with basic structure containing nitrogen atoms along with carbon, hydrogen, oxygen, sulfur, sometimes chlorine, bromine, and phosphorus. Alkaloids may include weakly acidic [25] or neutral [26] or few synthetic compounds, similar in structures [27]. Alkaloids are produced by proand eukaryotes and are known to have antimalarial-like quinine and antibacterial-like chelerythrine [28] activities. Marine macroalgae are rich sources of alkaloids, though few marine alkaloids of algal origin like those using phenylethylamine as precursors have been extracted from plants of terrestrial origin. Halogenated alkaloids from green algae (marine specific) and indole derivatives from red algae are specific. Algae of marine origin possess 44 types of alkaloids, 41 indole, 1 naphthyridine, and 1 phenylethylamine derivatives. Halogenated ones possess 25 bromine, 7 chlorine, and 5 sulfur components [29].
Marine fauna is a rich source of alkaloids, rather unique chemicals that inhibits enzyme enoyl-ACP reductase, a clinically relevant enzyme target from the type II fatty acid pathway of several pathogenic microorganisms. Several compounds related to bromopyrrole alkaloids have also been isolated from marine bacteria. A strain of marine Streptomyces is known to have A and B marinopyrroles, which are axially chiral and densely halogenated metabolites possessing an uncommon bispyrrole structure [30], significant because of their potent antibiotic properties against MRSA or methicillin-resistant S. aureus. A, B, C.
Marine sponges are very potent reservoirs of antimicrobially active natural sources of nitrogen-containing heterocyclic alkaloids like 1H-benzo [de] [1,6]-naphthyridine. Bromotyrosine alkaloids ceratinadins from Okinawan marine sponge belonging to Pseudoceratina sp., show N-imidazolyl-quinolinone moiety and antifungal potency [31]. A and B pseudoceratins, two bicyclic bromotyrosine-derived metabolites from Pseudoceratina purpurea [32], showed significant anti Candida albicans fungal activity. Two pyrroloiminoquinone alkaloids of class discorhabdin from sponge Sceptrella sp. from Gageodo, Korea [33] showed antibacterial potency, especially against enzyme sortase A, with a key role in anchoring of cell wall protein responsible for S. aureus virulence. 19-oxofasciospongine A and fasciospongine C (sulfated sesterterpene alkaloids) and 25-hydroxyhalisulfate 9 (sesterterpene sulfate), found recently and known sesterterpenes sulfates halisulphates 7 and 9, have been extracted from marine sponge Fasciospongia sp. organic extract [34], showed strong inhibitory hyphae -formation efficiency against Streptomyces 85E. Chinese marine sponge Iotrochota baculifera showed the presence of sulfated alkaloids baculiferins A-O and O-sulfated pyrrole alkaloids [35]. Of these, Baculiferins C, E e H, KeN efficiently inhibited HIV IIIB, by binding to targets viral infectivity factor (Vif), cellular deoxycytidine deaminase APOBEC3G and recombinant gp41, a trans-membrane protein. Caribbean sponge Monanchora unguifera shows the presence of guanidine alkaloids which are polycyclic with significant antimicrobial and antiviral properties [36] and batzelladine alkaloids like batzelladines K, L, M, N; 16 b-hydroxycrambescidin 359, ptilomycalin A, batzelladine C, crambescidine 800, and dehydrobatzelladine C with significant inhibitory activities against HIV and opportunistic pathogens of Acquired Immuno Deficiency Syndrome (AIDS). Merobatzelladines A, B isolated from this marine sponge is antibacterial [37]. Marine sponge Aaptos aaptos possesses alkaloid 4-methylaaptamine which shows inhibition against HSV-1 replication and antiherpetic activity [38]. Four aaptamines from A. aaptos show inhibitory activity against enzyme sortase A which is involved in S. aureus virulence and anchoring of cell wall protein [39]. Topsentin and hamacanthin are antimicrobial bisindole alkaloids isolated from marine sponge Spongosorites sp [40]. Dysideanins A and B from marine sponge Dysidea sp. are found to have antimicrobial potency [41]. 5-hydroxyindole-type alkaloids from Hyrtios sp. Sponges from tropical regions exhibited inhibitory potency against isocitrate lyase in C. albicans [42]. A family of alkaloids isonitrile-containing indole alkaloids, such as hapalindoles, have fused pentacyclic and hexacyclic carbon skeletons from cyanobacteria, are contemplated for use in pharmaceuticals. Fischambiguines A and B, ambiguine P, ambiguine Q nitrite, ambiguine G nitrite were isolated and identified from Fischerella ambigua [43]. Fischambiguine B showed antieMycobacterium tuberculosis activity. Diketopiperazine alkaloids are marine antimicrobial alkaloids. A marine halotolerant fungal strain -Alternaria raphani from sea salt fields showed the presence of cerebrosides, alternarosides A, B, C, and diketopiperazine alkaloid, alternarosin A [44], which show weak antibacterial activity against Escherichia coli, Bacillus subtilis and C. albicans. Caboxamycin produced by deep-sea Streptomyces sp. NTK937 showed inhibitory activity against Gram-positive bacteria [45].

Peptides
Marine antimicrobial peptides are present in all living species and build up their defense mechanisms. They probably act as humoral natural humoral defense in invertebrates, also termed as "natural antibiotics" [46]. Cyclodepsipeptides are marine peptides found in sponges exhibiting antiviral and antimicrobial potencies [47]. Cyclic peptides family includes unique N-terminal polyketide-derived molecules and diverse types of unusual amino acid residues.
Cyclic depsipeptides Papuamides from marine sponges have shown in vitro cytoprotective activity for HIV, preventing entry of the virus. Antiviral cyclic depsipeptides -mirabamides A, B, C, D are isolated from sponge Siliquariaspongia mirabilis [48], probably preventing HIV fusion. Mirabamides are composed of 4-chloromoproline in 1, 2, 3 positions, b-methoxytyrosine 4 0 -O-a-L-rhamnopyranoside (unusual glycosylated amino acid) in 1, 2, 4 positions and rare N-terminal aliphatic hydroxy acid. Mirabamide A, C, D is found to inhibit HIV acting at entry stage of HIV. Mirabamides A, B, C inhibit Bacillus subtilis and C. albicans. Alternaramide, a cyclic depsipeptide from the marine fungus Alternaria sp. SF-5016 [49] exhibited weak anti S. aureus and anti Bacillus subtilis activity. Homophymine A, a cyclodepsipeptide from marine sponge Homophymia sp [50]. showed anti -HIV cytoprotective potency. Homophymime A is composed of 11 amino acids, an amide-linked-3-hydroxy-2, 4, 6-trimethyloctanoic acid molecules; four Dextro, two Levo, one N-methyl amino acids and four unusual amino acid residues. Callyaerins A, B, C, D, E, F and H are antiviral and antimicrobial peptides from marine sponge Callyspongia aerizusa [51]. Theonellamides are bicyclic peptides from marine sponges which show antifungal activities [52]. Aminolipopeptides, Trichoderins A, A1 and B, are marine antimicrobial peptides from sponge -derived fungus of Trichoderma sp. They show antimycobacterial activity versus dormant and active marine bacilli [53], especially against Mycobacterium tuberculosis, M. Smegmatis and M. bovis. Anthranilic acid and dehydroamino acid units, sclerotides A and B, components of cyclic hexapeptides obtained from marine halotolerant Aspergillus sclerotiorum PT06-1 [54] exhibited antibacterial and antifungal activities. Aspergillus sclerotiorum PT06-1 was found to contain cyclic tripeptides scleraotiotides A-K of aspochracin nature [55]. Sclerotiotides A, B, F, I showed antifungal activity for C. albicans. Maribasins A and B cyclic lipopeptides, from marine Bacillus marinus B-9987 showed broad-spectrum activity against phytopathogens [56]. Two antifungal lipopeptides on eof which is the rare 6-Abu fengycin lipopeptides from marine Bacillus amyloliquefaciens SH-B10 [57] showed remarkable inhibitory potency against five phyto-fungal pathogens, suggesting bio-control and sustainable agricultural practicese. Tauramamide, lipopeptide from marine bacteria Brevibacillus laterosporus PNG276 [58] along with ethyl ester 3, showed selective inhibitory activity against pathogenic species of Enterococcus. Thiopeptides and depsipeptides are marine bacterial antimicrobial peptides found in Nocardiopsis sp. TP-1161 [59], possessing a unique aminoacetone group. Unnarmicine A and C, marine depsipeptides from Photobacterium MBIC06485 [60] selectively killed two Pseudovibrio species, commonly existing in marine environment. Hybrid forms of marine peptide polyketide-nonribosomal antimicrobial agents from Myxobacteria have been isolated. One example is halophilic myxobacterium Paraliomyxa miuraensis, producing miuraenamides A and B which are hybrid cyclic polyketide-peptide antimicrobial agents [61]. Two rare hybrid polyketide-nonribosomal linear peptide antibiotics, Ariakemicins A and B found in marine gliding bacterium Rapidithrix species [62], are found to be composed of two U-amino-(U-3)-methyl carboxylic acids with diene or triene units, threonine and d-isovanilloylbutyric acidand inhibited particularly Gram-positive bacterial growth. Nonribosomal peptides from marine Brazilian cyanobacterial isolates are antimicrobial [63], while from Brevibacillus laterosporus Lh-1 exhibit antimicrobial activity for fungi and Gram-positive and Gram-negative bacteria [64].

Carbohydrates
Carbohydrates are biomolecules present in abundance, in the form of cellulose and chitin, glycogen and starch acting as great energy sources and cellular recognition molecules, at cell surface [65]. They are structurally complex with dynamic properties, structural fluctuations, large diversity of units due to umpteen enantiomers, various glycosidic bonds and modifications after polymerization. The diverse classes of carbohydrate classes consist of negatively charged neutral and neutral saccharides of different lengths [66]. Marine carbohydrate compounds are chemically diverse with glycosidic domains and exhibit various biological properties and functions which may help in their implementation in bioactive products. Many are the known applications of substances obtained from marine species. Their activities include antioxidant, antiinflammatory, anticoagulant, antitumor, and antimicrobial potencies. This may utilize them for their nutritional and therapeutic potential, though they are the most poorly explored but promising molecules. Many of them are being clinically tried out for possible potential for antiviral therapies [67]. Their biological roles include significant pharmacological potencies like antiinflammatory [68], antiviral [69], cellular interactions [70], and pathogen recognition [71]. glucose (Glc) residues with less than 10% of single b-D-Glc residues branches attached to C-6 of backbone Glc residues [72], Type G with chains terminated by D-Glc residues, and Type M -with chains ending with D-mannitol (Man) residues [73].
They show antiinflammatory activity [74]. Laminaran enhances release of few inflammation mediators, thus being immunostimulatory and antiinflammatory [75]. Laminaran, a marine glycan inhibits both Gram-positive and Gram-negative marine bacteria such as Vibrio parahaemolyticus, Listeria monocytogenes, and Salmonella typhimurium. It prevents HIV virulence by decreasing its adsorption in human lymphocytes, reducing the efficiency of HIV enzyme reverse transcriptase, thus preventing HIV replication and multiplication [76]. b) Alginic acid: It is a marine polysaccharide extracted from brown algae, with a broad spectrum of medicinal, food, biotechnological, and industrial applications [77].
Brown algae Sargassum wightii species show alginic acid with antioxidant and antiinflammatory activities, reducing many cyclooxygenase, lipoxygenase, and myeloperoxidase enzyme activities, C-reactive protein levels, rheumatoid factor and ceruloplasmin along with lipid peroxidation reduction and enhanced enzyme activity [78]. The antioxidant activity of alginic acid is because of its metal chelating capacity, scavenging of free radicals, reducing tissue ferric ions and enhancing antimicrobial potency [79]. It controls Listeria monocytogenes growth, responsible for serious food infections [80].

N-acetylated sugars
Chitin and Chitosan: Chitin is present in organism's exoskeletons like crustaceans and insects. It is biopolymer and found abundance in marine environment, structurally made up of GlcNAc, GlcN units linked by b-1, 4 glycosidic bonds. GlcNAc is strongly N-acetylated due to the presence of more than 70% of total monosaccharides, decreasing its water solubility. Chitin has 4-linked N-acetyl Glucosamine (GlcNAc 2-acetamido-2-deoxy-D-b-glucose) units and partly glucosamine, GlcN (2-amino-2-deoxy-b-D-glucose) units. In case of less than 50% GlcNAc content or DA -degree of N-acetylation, the polymer is called Chitosan. Chitosan, a cationic polysaccharide, is made up of repeating units with chitin glycosidic linkages, but less than 50% levels of GlcNAc. Their interactions and hydrophobicity depends on number and positions of acetyl groups [103]. Due to non-toxicity, it can be biomedically applied for special functions like antipathogenic activity [104], decided by its molecular weight, extent of deacetylation and substitution, pH, length of substituents and their positions in GlcN units [103].

Triterpene Glycosides
Triterpene Glycosides are amphiphilic with a sugar molecule (mono-or oligosaccharide) linked to a functional group (terpene or flavonoid or other natural molecules) with a glycosidic bond [68]. They are highly diverse in nature.

Glycoproteins
Glycoproteins are a big class of biomolecules, present in cell membranes. Glycoprotein glycoconjugates have a protein backbone to which different monosaccharides are covalently attached. Glycoproteins contain N-linked sugar chains (GlcNAc group at reducing end attached to amide group of asparagine residue of polypeptide backbone) and O-linked sugar chains (GalNAc at reducing nd, attached to hydroxyl group of Serine (Ser) or Threonine (Thr) groups of polypeptide backbone) [114].
Glycoproteins act as receptors capturing ligands into cells like transport proteins responsible for ingestion of nutrients, structures mediating molecular recognition, molecular signaling and cellular interactions [99].
Mannose-specific Lectin from Green alga Halimeda renschii showed strong activity against influenza virus due to high affinity binding to hemagglutinins on envelopes of viruses [115].

Glycolipids
Glycolipids, amphipathic in nature, are a diverse and large lipid group, containing a hydrophilic portion with carbohydrate units, from which its prefix "glyco" is derived. The lipid portion is the hydrophobic tail, with aliphatic chains of fatty acids [116]. Glycosphingolipids are a class of glycolipids, which constitute cell membranes in marine or terrestrial organisms [117]. Their action is because of variations in sugar chains, based on which they are classified as cerebrosides, ceramide oligohexosides, globosides and gangliosides.

Iminosugar
These are natural aza or imino monosaccharides in which nitrogen replaces oxygen in ring structure. Nojirimycin, a 5-amino-5-deoxyglucose antibiotic, was first to be isolated and characterized in 1960. Later, more than 25 analogues of nojirimycin were studied in plant and microbes [120].
Iminosugars show nematicidal [121], antiviral [122], and insecticidal [123] activities because of their glycosidase potency, interfering with processing of glycoprotein. 1-Deoxynojirimycin iminosugar with Glc inhibits synthesis of infective viruses such as dengue (DENV), hepatitis B, hepatitis C, HIV, and influenza A viruses because of virus release inhibition due to inhibition of endoplasmic reticulum a-glycosidases [124]. Batzellasides A, B, and C are extracted from Batzella sp. sea sponge, consisting of an iminosugar nucleus with a long chain of alkyl substituent. Batzellasides differ in the lengths of alkyl chains. Batzellasides A, B, and C show inhibition of Staphylococcus epidermidis [120].

Fatty acids
Marine fatty acids in marine organisms possess biological properties such as antiviral and antimicrobial potencies.
Paragrantia cf. waguensis, a calcareous sponge, possesses acetylenic fatty acid [125], exhibiting antimicrobial activity against E. coli and S. aureus. Brominated unsaturated fatty acids from marine sponge showed antimicrobial fatty acids [126]. Motualevic acids A, B, C, D, E, and F from marine sponge Siliquariaspongia sp. have shown inhibitory potency toward S. aureus and MRSA [127]. Marine algae diatom Phaeodactylum tricornutum has shown antibacterial activity, which was due to unique (6Z, 9Z, 12Z)-hexadecatrienoic acid, a polyunsaturated fatty acid, and (9Z)-hexadecenoic acid, a monounsaturated fatty acid [128], both of which are inhibitory toward Gram-positive bacteria and marine pathogen Gram-negative Listonella anguillarum (9Z)-hexadecenoic acid kills bacteria at great speed, showing potent activity against multidrug-resistant strains of S. aureus. P. tricornutum produces eicosapentaenoic acid, an antibacterial fatty acid inhibitory toward a range of Gram-positive and Gram-negative bacteria, as well as multidrug-resistant S. aureus [129]. Asperamides A and B, a sphingolipid and their corresponding glycosphingolipid possessing a 9-methyl-C20-sphingosine moiety, from A. niger EN-13, an endophytic fungus from marine brown alga Colpomenia sinuosa [130], showed inhibitory action against C. albicans. Marine fungi are of great importance as potential sources of agricultural pesticide leads such as unsaturated fatty acid glycerol esters, asperxanthone and asperbiphenyl, extracted from marine fungus Aspergillus sp. MF-93 [131], active against tobacco mosaic virus.

Polyketides
Polyketides can be defined as natural secondary metabolites used in human therapy as antibiotics and antifungal agents. Classical examples are nystatin, amphotericin, and rapamycin antibiotics. Polyketides such as polycyclic ether macrolides and open-chain polyketides are produced and stored by marine sponges and show strong antiviral and antimicrobial activities.
Marine fungal Nigrospora sp. PSV-F18 and PSU-F5 showed the presence of nigrosporapyrones A, B, C, and D and nigrospoxydons A, B, and C, which are antimicrobial macrolides [137].

Polysaccharides
Polysaccharides are structurally very diverse biological macromolecules because of presence of various sugars and their derivatives such as uronic acid. In nature, each sugar is linked covalently to another sugar at different sites in the sugar ring. Marine plants, animals, organisms, bacteria, and fungi are a source of a large diverse variety of polysaccharides [138], some of which exhibit antiviral and antimicrobial actions.
Edible Nostoc flagelliforme, a species of blue-green alga, shows nostoflan, an acidic polysaccharide which shows antiviral activity (anti-HSV-1) [139], inhibiting virus binding. Lectin is a marine polysaccharide from Oscillatoria agardhii NIES-204, a filamentous cyanobacterium inhibiting HIV replication in MT-4 cells [140]. Chitinase is a marine antifungal polysaccharide from marine South China sea sponge inhibiting Streptomyces sp. DA11. Craniella australiensis exhibited antifungal defense activity for C. albicans and A. niger [141], which may be because of its microbial symbiont exhibiting chitinase activity bringing about chitin degradation.

Phenolic compounds
The vastest group of secondary metabolites in plants is the group of phenols. It is naturally spread wide and present in natural compounds with aromatic moieties. They have a wide range of structures from simple one aromatic ring structure to extremely complex polymeric compounds. Commonly, in marine regions, phenolic compounds with halogens as moieties occur in high frequency. Marine sponges exhibit phenolic compounds, which are studied commonly for antimicrobial activity.

Steroids
Steroids are natural products which are glycosides in nature and marine or terrestrial in origin. Many glycosides exhibit various biological activities including antimicrobial.

Antimicrobial drugs of marine origin under clinical trials
There are various marine originating chemical antimicrobial lead compounds which can be further explored for human health issues. There are currently over 3000 new substances identified from marine organisms in the past three decades, giving researchers a large pool of novel molecules from which to find new compounds to develop [158].
They have to be clinically tried out before being implemented for general prescriptions. This requires ample amounts of compounds under trial to be isolated and extracted in pure forms from the source. Obtaining them from invertebrates in sufficient amounts can prove difficult. There are various such compounds that are presently under clinical trials. Aqua culture is an alternative but may not be viable in all cases. Microorganisms may be used as sustainable sources for production of required compounds for production of intermediates in the first step of semisynthesis which can later produce final compound of interest.

Antibacterial compounds under clinical trials
In the era of rapid emergence of antibiotic-resistant bacteria, marine sponge extracts have shown the best antimicrobial potency against terrestrial bacteria [159]. When 101 arctic sponges were antimicrobially screened against opportunistic infections causing bacteria, approximately 10% of them showed significant results, values of IC50 ranging from 0.2 mg/mL to 5 mg/mL [160]. About 800 compounds with antibiotic properties have been isolated and identified from marine sponges [161]. Of 31 sponges checked, 18 showed strong antimicrobial potency against Gram-positive and Gram-negative bacteria and are being screened for a range of therapeutically significant substances [162]

Antiviral compounds under clinical trials
No cure has yet been available for adenovirus serotype 5 (AdV-5) associated with respiratory infections [166] or rotaviruses associated with severe gastroenteritis of animals and humans or diarrhea in immunocompromised patients, which may prove fatal [167]. About 40 antiviral substances from marine species have been reported, half of which have shown prospects in treatment of HIV infection. On this background, marine sponges, sources of novel antivirals, may prove to be good therapeutic agents [168]. Avarol inhibits HIV infection progression and increases humoral immune response. Avarol in 0.3, 0.9 mM concentration inhibited 50%, 80% of viruses, respectively, released by infected cells [169]. Avarol derivatives, 6 0 -hydroxyavarol and 3 0 -hydroxyavarone, strongly inhibit HIV reverse transcriptase in HIV.
Avarol converts viral genomic RNA to proviral DNA and integrates it in host chromosomal DNA [170]. Various antiviral marine metabolites are currently under clinical trial. Examples of antiviral compounds under clinical trials are the following: l 4-Methylaaptamine is an alkaloid from A. aaptos inhibitory toward HSV-1 [38].

Antifungal compounds under clinical trials
Invasive mycoses, an increasing resistant fungal infection in patients of AIDS, on immunodepressants, with blood cancers, undergoing transplants [179], have proved fatal. Candida, Aspergillus, Cryptococcus, and other opportunistic fungi are common culprits. Sponges belonging to Jaspis sp. have given Jaspamide cyclodepsipeptide, a 19-unit macrocyclic depsipeptide, exhibiting in vitro antifungal potency against C. albicans [180]. Examples of antifungal compounds under clinical trials are the following: l Jaspamide, a macrocyclic depsipeptide from Jaspis sp., has shown an MIC against C. albicans of 25 mg/mL [180].
l Mirabilin B is a tricyclic guanidine alkaloid, from M. unguifera, acting against C. neoformans, with an MIC of 7.0 mg/ mL [36].
l Hamacanthin A is an indole alkaloid, from Spongosorities sp., active against C. albicans, with an MIC of 6.25 mg/mL [182].

Antimalarial compounds under clinical trials
Plasmodium vivax, the predominant malarial parasite, has caused havoc by spreading malaria in vast areas of Asia and America, while showing accelerating antibiotic resistance. A need for new antimalarial compounds led to antimicrobial agents from marine sponges. Cymbastela hooperi has exhibited antimalarial potency against P. falciparum through isonitriles, terpenoid isocyanates, and isothiocyanates [184]. Diacarnus megaspinorhabdosa, a marine sponge exhibited antimalarial potency toward chloroquine-resistant and -sensitive P. falciparum through epidioxy-substituted norsesterterpenes and norditerpene endoperoxides [185].  [185]).

Future outlook and conclusion
Natural products have always played a significant role in drug discovery for treating human diseases. Drugs developed from marine sources have ignited a hope to offer novel mechanisms to fight some of the most debilitating diseases such as HIV, osteoporosis, Alzheimer's, and cancer. Although costs required for developing drugs from marine sources have been exorbitant, development of new technology and better understanding of marine species and associated ecosystem has helped us in developing research in the area of drug development. Bright future awaits pharmaceutical industry for developing new drugs from antimicrobial lead compounds obtained from marine sources. The progress is slow, but surely drug manufacturing units have started showing interest in implementing natural marine sources for drug developing. A future trend is developing in research today, positively toward use of marine natural resources. There are ample of marine lead compounds, more than imagined [192].
Metabolites derived from marine species such as sponges span wide with respect to their chemical components such as alkaloids, peptides, terpenoids, polyketides, and others, with a variety of antimicrobial and other properties [187]. When these compounds are prepared for the market, they need to have a known chemistry, enhanced bioavailability, and minimized side effects. Manzamines are metabolites from marine sponges that can be potentially used as drugs against tuberculosis [193], HIV [169], malaria [184], and others. Ara-A, ara-C, and acyclovir are a few products originating from marine sponges in clinical use [169].
It has been observed that medicines derived from various metabolites and derivatives from marine species such as sponges possess their efficiencies as medicines, based on their doses, qualitative, and quantitative effects of inhibition and their other effects. Besides, they are present in the marine species in very low quantities, which presents difficulties in their being reproduced in ample amounts in the market. Avarol, obtained from sponge D. avara sponge, is an efficient drug for treatment of HIV [169], which could not be available for studies further than preclinical ones because of its low availability for assessment [194]. Another advantage of marine species metabolites is that their carbon skeletons can be used as carriers or vehicles for generating efficient derivatives. Mankind now faces a challenge of preparing the miracle drugs in large quantities, transforming bioactive metabolites to medicines by selecting proper marine species, isolating the correct metabolite, with its precise action and its target point toward a disease.
Although marine environment has umpteen numbers of species which are natural resources for antimicrobial compounds, very few of these secondary metabolites have reached the stage of being approved as drugs, while some metabolites and their derivatives are still under clinical trials or preclinical trials at various stages.
These trials require a large amount of these metabolites, which has lead to novel ideas like chemically modifying marine natural products or MNPs to transform them into "druglike" products, farming organisms in natural environment, and culturing organisms artificially [195]. Preclinical trials need very systematic, detailed pharmacokinetic investigation to tailor MNPs, a challenging task. Antimicrobial efficiency of marine metabolites has shown a promising future for development as human therapeutic agents. A revolution has been set up because of the technique of genome mining for natural product discovery. Technology is being targeted optimally for drug research, its approvals and its launches, for the betterment of human life. This chapter has attempted to give a sketch of antimicrobial lead compounds from marine species, a step forward toward the development of medicinal and biological agents from marine natural sources. This may be an endeavor toward exploring an untrodden path in drug discovery, from marine environment, for the global health benefits of mankind.