Antibiotics Derived From Marine Organisms

Antibiotics Derived From Marine Organisms

Chapter 10 Antibiotics Derived From Marine Organisms: Their Chemistry and Biological Mode of Action Bibi Nazia Auckloo, Bin Wu1 Ocean College, Zhejia...

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Chapter 10

Antibiotics Derived From Marine Organisms: Their Chemistry and Biological Mode of Action Bibi Nazia Auckloo, Bin Wu1 Ocean College, Zhejiang University, Hangzhou, China 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction Sources of Marine Antibiotics Marine Invertebrates Marine Sponges Marine Microorganisms (Bacteria and Fungi) Chemistry and Activities of Marine Antibiotics Protein/Polypeptide Polyketide/Macrolactones Anthroquinone Class Polybrominated Biphenyl Class

483 485 485 485 486 487 487 497 500 501

Terpenoid Class Alkaloid Class Mode of Action Disruption of Membrane Leading to Restriction of DNA Synthesis Inhibition of Bacterial RNA Polymerase Quorum Sensing Manipulation/Inhibition Opinion and Conclusion References

502 504 506

506 507 509 510 511

INTRODUCTION The ocean covers 70% of the Earth’s surface accommodating approximately 87% of life on the planet. The marine biosphere offers a wide range of invaluable and unique compounds which possess diverse biological properties [1,2]. A great number of natural products originate directly from marine animals such as sponges, cnidarians, and mollusks while some arise from microbes like bacteria or fungi which are linked to other organisms or dwell in Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00010-3 Copyright © 2016 Elsevier B.V. All rights reserved.

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marine sediment. According to the database created by Hu et al. [3], a pool of 12,322 new compounds has been isolated from marine organisms from 1985 to 2008. Further inquiries by Blunt et al. [4e7] revealed an increase in isolation of new compounds from marine organisms accounting a total of 6948 from 2009 to 2014. The structural miscellany and biochemical distinctiveness of natural products derived from marine origin surpasses to a high extent the ones from terrestrial origin, thus are considered as potential candidates in the development of novel and beneficial agents for medical applications [8e12]. Microorganisms striving under specific circumstances such as extreme variations in temperature, pressure, salinity, dissolved oxygen, and nutrients availability generate antimicrobial or antibiotics having vast inhibitory potential against harmful gram-positive as well as gram-negative bacteria [13]. Anaerobic bacteria have long been neglected until the isolation of the prime antibiotic closthiamide from Clostridium cellulolyticum [14] which lead to the application of genetics in revealing the anaerobic world [15]. Besides acting as antibacterial agents, marine bacteria were noted to generate compounds such as Salinosporamide A which was shown to be a proteasome inhibitor in clinical trial [16], marinomycins which have the ability of acting as antitumor antibiotics [17], apratoxin A exhibiting anticancer capacities [18]. More information can be accessed in Ref. [19]. Compared to natural products isolated from terrestrial sources, a huge number of marine microorganisms producing significant natural products have long been underexplored due to the difficulty in their cultivation and isolation in the laboratory [20]. In the past years, it has been shown that there was a continuous decline in isolation of effective antibacterial compounds due to increased research expenses, unavailability of sophisticated methodologies which could be able to identify new promising compounds, lack of expertise, and manpower, as well as lack of freedom to carry out researches due to regulatory barriers. As a matter of evolution, pathogens mutate at a rapid pace, thus modifying its genetic materials which boost up its capacity of becoming more resistant by acquiring metabolic power [21]. Consequently, a major threat to humanity which is on the top priority list worldwide is the resistance of bacteria to antibiotics which is drastically escalating the rate of patients with infectious diseases. For instance, two million deaths are recorded as a result of bacterial infections around the world. For the very first time, the World Health Organization (WHO) has organized the “World Antibiotic Awareness Week” which was held from 16 to 22 November, 2015 in order to reveal information about antibiotic resistance for its good use in the future [22]. Therefore, it is a matter of life and death to engage in the development of new promising drugs and going through the “antibiotic era” once again. This chapter will focus mainly on the antibiotics produced by marine organisms, their related chemistry and antibacterial activities either in vitro or in vivo as well as their mechanisms of action where available.

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SOURCES OF MARINE ANTIBIOTICS As mentioned above, the ocean is an untapped source of scaffolds with unique products which further encouraged researches in the isolation of promising antibacterial compounds which could be developed and clinically tested for therapeutic remedies and medical purposes. Marine organisms are usually divided into three main groups namely plankton, nekton, and benthos where all possess a wider molecular diversity compared to terrestrial organisms due to their prolonged evolutionary history [23].

Marine Invertebrates From previous studies, marine invertebrates comprising about 60% of marine fauna [24] were seen to generate bioactive natural products which can be considered as beneficial therapeutic agents for human, with more information available in Ref. [25]. Based on the investigation carried out by Leal et al. [26], almost 10,000 new marine natural products were isolated from invertebrates since 1990 to 2009 with the most ubiquitous origins being from Porifera and Cnidaria. However, this section will focus mainly on the isolation of antimicrobial peptides from marine invertebrates followed by antibacterial compounds from marine sponges. Marine invertebrates have a specific mechanism in defending themselves against invasive microbes by the innate immune system comprising of both the cellular (encapsulation or phagocytosis) and humoral (antimicrobial agents in blood cells and plasma) reactions [27]. This innate immune system permits the formation of antimicrobial peptides (about 10 ;kDa) which can be classified as a-helices, b-sheet, or small proteins [28]. Due to resistance of bacteria to previous known antibiotics, antimicrobial peptides exerting a vast array of toxicity to pathogens are paving the way into pharmaceutical industries and research institutions in order to be developed as prospective antibiotics for future use [29e31]. Some antimicrobial peptides which have been demonstrated to act against pathogenic microorganisms are myticusin-1 which was isolated from Mytilus coruscus mussels in China [32], and myxinidin isolated from the hagfish Myxine glutinosa L. found in Canada [33] which are both discussed below.

Marine Sponges Marine sponges from the phylum Porifera are considered as the most primeval organisms dwelling in a wide range of marine ecosystems in temperate, polar, and tropical regions [34]. These multicellular, sessile invertebrates account for approximately 15,000 species discovered till now with a diversity in their morphological appearance mainly shapes and colors [35]. Sponges are generally exposed to many predators among them being pathogenic microorganisms and despite the fact that they are immobile, these unique marine

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organisms have developed chemical defenses by producing and releasing specific compounds for protection and for space competition purposes [36,37]. From 2010 to 2014, numerous tremendous secondary metabolites isolated from marine sponges have been discovered accounting for a total of 1460 [4e7]. Sponges generate a diversity of substances which can be classified in different chemical classes such as peptides, terpenes, or alkaloids [38e45] with promising antibacterial activities [46e49]. Sponges from different part of the world such as Brazil [50,51], New Zealand [52], or France [53] have revealed strong antimicrobial effect against both gram-positive and gramnegative bacteria. According to previous work, about 800 antibiotic substances have been identified from marine sponges [54]. Some examples include manoalide isolated from Luffariella variabilis [55], axinellamine B, axinellamine C, axinellamine D [56], and petrosamine B [57] from the Australian Axinella sp., and Oceanapia sp., respectively. Moreover, haliclonacyclamine E and arenosclerin A, B, and C from Arenosclera brasiliensis found in Brazil showed antibiotic impact on 11 antibiotic-resistant bacteria [54]. The manzamine-type alkaloids (12, 34-oxamanzamine E, 8-hydroxymanzamine J, and 6-hydroxymanzamine E) derived from the Indonesian Acanthostrongylophora species [58] also displayed promising results which make them potential candidates for the future.

Marine Microorganisms (Bacteria and Fungi) Since the discovery of the first antibiotic namely penicillin by Alexander Fleming in 1929, terrestrial microorganisms has been the chief focus of research. Due to a high duplication rate of metabolites isolation from the soil, pathogens increased resistance and upsurge in infectious diseases; marine microorganisms have now become the spotlight of researchers worldwide. Soil actinomycetes are exceptional prokaryotes which were seen to produce a great number of unique natural products among which is antibiotics [59]. Nowadays, marine actinobacteria are considered as a fruitful generator of potent natural products which can be beneficial in the pharmaceutical industry [60]. Due to the completely different marine conditions, marine actinomycetes were shown to display wider genetic and metabolic diversity leading to the production of novel metabolites [60e63]. However, a strong point to be noted is that there is uncertainty about the source indigenous marine actinomycetes populations which might have been transported from land to the sea [64,65]. Cultivation methodologies used in the laboratory have shown that actinomycetes dwell in every part of the ocean from the deep sea to living in symbiotic relationship with some other marine organisms [66]. Marine bacteria have proved themselves in producing novel interesting secondary metabolites which are efficacious against some pathogenic microbes. For instance, abyssomicin C isolated from the Verrucosispora strain from marine sediment at a depth of 289 m [67], diazepinomicin (ECO-4601) generated from Micromonospora

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strain obtained from the marine ascidian Didemnum proliferum [68], hormaomycin B and C isolated from actinomycete strain (SNM55) from marine sediment in Korea [69] as well as lobophorin E and F obtained from the actinobacterial strain SCSIO 01,127 in the South China Sea sediment [70] revealed persuasive antibacterial capabilities. Together with marine bacteria, marine fungi also have the skills to yield antimicrobial agents such as the antibiotic pestalone produced from a mixed culture of marine fungus (strain CNL-365, Pestalotia sp.) obtained from the phaeophyta Rosenvingea sp. in the Bahamas Islands and an unidentified, antibiotic-resistant marine bacterium [71] as well as terretonin G isolated from the fungus Aspergillus sp. OPMF00272 from poriferan in Japan [72]. Furthermore, three new chlorine containing antibiotics (8-chloro-9-hydroxy8,9-deoxyasperlactone, 9-chloro-8-hydroxy-8,9 deoxyasperlactone, and 9-chloro-8-hydroxy-8,9-deoxyaspyrone) had been isolated from the fungus Aspergillus ostianus strain TUF 01F313 obtained from an unidentified marine sponge at Pohnpei showed fascinating inhibitory effects on the marine bacterium Ruegeria atlantica [73]. Two new oxaphenalenone dimers, talaromycesone A and B isolated from Talaromyces sp. strain LF458 obtained from the tissues of the sponge Axinella verrucosa at 20 m deep in the Mediterranean Sea also revealed effective antibacterial activities [74]. Table 10.1 gives a summary of antibiotics and/or antibacterial agents derived from marine organisms.

CHEMISTRY AND ACTIVITIES OF MARINE ANTIBIOTICS So far, terrestrial antibiotics have been found to possess diverse mode of action acting on different types of pathogens and researchers are now going in more details about the specific mechanisms in order to maneuver imminent treacherous bacteria using marine antibiotics. Previous studies focused mainly on the elucidation of the chemical structures of novel antibacterial compounds from the ocean and limited works have been carried out on the detailed mode of action of the marine antibiotics. This part will give you an insight of the recent works done, the various chemical classes of antibiotics, the bioactivities, and mode of action of some marine antibiotics displaying the countless benefits of marine natural products, which can be used to path the way for a better future without infectious diseases.

Protein/Polypeptide The Lactococcus lactis strain PSY2 isolated from the surface of marine yellow perch fish Perca flavescens exhibited antibacterial activities against grampositive and gram-negative bacteria namely Arthrobacter sp., Acinetobacter sp., Bacillus subtilis, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Staphylococcus aureus. It was seen that the shelf-life of the

Chemical Class

Source

Protein/ polypeptide

Mussel Mytilus coruscus

Isolated Compound

Potential Target

Mode of Action

Reference

Myticusin-1

Bacillus subtilis, Staphylococcus aureus, Sarcina luteus, and Bacillus megaterium

Act on cell wall

[32]

Hagfish Myxine glutinosa L.

Myxinidin

Salmonella enterica serovar Typhimurium C610, Escherichia coli D31, Aeromonas salmonicida A449, Yersinia ruckeri 96-4, and Listonella anguillarum 02-11

d

[33]

Actinomycete strain (SNM55)

Hormaomycin B and C

Kocuria rhizophila NBRC 12708

d

[69]

Lactococcus lactis strain PSY2

Bacteriocin PSY2

Arthrobacter sp., Acinetobacter sp., B. subtilis, E. coli, Listeria monocytogenes, Pseudomonas aeruginosa, and S. aureus

d

[75]

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TABLE 10.1 Summary of Antibiotics/Antibacterial Agents Derived From Marine Organisms

Hc-cathelicidin

Dislocate the pathogen’s cell membrane

[76]

Oyster Crassostrea madrasensis

C. madrasensis protein

Vibrio cholerae, Vibrio parahaemolyticus, Salmonella sp., Shigella sp., Streptococcus sp. and Staphylococcus sp.

d

[77]

Actinomycete strain (CNS-575)

Etamycin

Hospital- and community-associated methicillin-resistant S. aureus, Streptococcus pyogenes, Streptococcus agalactiae, coccobacilli, Moraxella catarrhalis

Obstruction of protein synthesis in bacterial cells

[78]

Marine sponge Neamphius sp.

Neamphamide B

Mycobacterium smegmatis

d

[79]

Streptomyces sp. CNB-091

Salinamide A

Enterobacter cloacae ATCC 13047 and Haemophilus influenza ATCC 49247

Inhibition of bacterial RNA polymerase

[99]

Streptomyces sp. CNB-091

Salinamide F

S. aureus, E. coli, Enterococcus faecalis, H. influenza, Neisseria gonorrhoeae, E. cloacae

Inhibition of bacterial RNA polymerase

[100]

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Sea snake Hydrophis cyanocinctus

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Continued

Chemical Class

Source

Polyketide/ macrolactones

Marine Verrucosispora strain

Isolated Compound

Potential Target

Mode of Action

Reference

Abyssomicin C

Methicillin-resistant S. aureus

Restrict the biosynthetic precursor of folic acid

[67]

Actinobacterial strain SCSIO 01127

Lobophorin E and lobophorin F

S. aureus ATCC 29213, E. faecalis ATCC 29212 and Bacillus thuringensis SCSIO BT01

d

[70]

Talaromyces sp. strain LF458

Talaromycesone A and B

Staphylococcus epidermidis and the methicillin-resistant S. aureus

d

[74]

B. subtilis MTCC 10403

7-O-methyl-50 -hydroxy30 heptenoateemacrolactin

Aeromonas hydrophila, V. parahemolyticus ATCC 17802

Affect the lipophilic membrane

[82]

Streptomyces sp. JRG-04

Aromatic polyketide compound 4

S. aureus MTCC 3160

Disrupt the cell membrane

[83]

Bacillus sp. 09ID194

Macrolactins X, Y, Z

B. subtilis (KCTC 1021), E. coli (KCTC 1923), and Saccharomyces cerevisiae (KCTC 7913)

d

[84]

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TABLE 10.1 Summary of Antibiotics/Antibacterial Agents Derived From Marine Organismsdcont’d

Polybrominated biphenyl class

Macrolactin S

E. coli, S. aureus and B. subtilis

d

[85]

Fungal strains KF970 and LF327 from the family Lindgomycetaceae obtained from a marine sponge

Lindgomycin and ascosetin

B. subtilis, S. epidermidis and methicillin-resistant S. aureus

d

[86]

Streptomyces cyaneofuscatus M-27

Cosmomycin B

d

d

[87]

Streptomyces sp. (CMB-M0150)

Aranciamycin I and Aranciamycin J

Mycobacterium bovis BCG, B. subtilis

d

[88]

Pseudomonas stutzeri

Zafrin

S. aureus, and Salmonella typhi

Destructive effect on the cytoplasmic membrane

[89]

Pseudoalteromonas phenolica sp. O BC30T

MC21-A 1

Render the cell membranes of bacteria permeable

[90]

P. phenolica O-BC30T

MC21-B 2

Disruption of the cell wall or cell membrane of the pathogens

[91]

Methicillin-resistant S. aureus, B. subtilis and Enterococcus serolicida

Continued

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Anthroquinone class

Bacillus sp.

491

Chemical Class

Terpenoid class

Isolated Compound

Potential Target

Mode of Action

Reference

Sponge Luffariella variabilis

Manoalide

d

d

[55]

Fungus Aspergillus sp. OPMF00272

Terretonin G

S. aureus FDA209P, B. subtilis PCI219 and Micrococus luteus ATCC9341

d

[72]

Red sea sponge named Prianos sp.

Prianicin A and prianicin B

Beta hemolytic Streptococcus

d

[92]

Strain CNQ-525 (genus: Tentatively called MAR4)

Chlorine-containing terpenoid dihydroquinones

Methicillin-resistant S. aureus, Vancomycin-resistant Enterococcus faecium

d

[73]

Soft coral Sarcophyton trocheliophorum

Sarcotrocheliol acetate and sarcotrocheliol

S. aureus, Acinetobacter spp., and MRSA

d

[93]

Acanthella cavernosa

10- And 15-formamido-kalihinol F

d

Inhibit bacterial folate (cofactor for metabolic processes) biosynthesis

[94]

Source

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TABLE 10.1 Summary of Antibiotics/Antibacterial Agents Derived From Marine Organismsdcont’d

Alkaloid class

Axinellamine B, axinellamine C, axinellamine D

Helicobacter pylori

d

[56]

Sponge Oceanapia sp.

Petrosamine B

H. pylori

Ability to inhibit the enzyme aspartate semialdehyde dehydrogenase needed for protein synthesis

[57]

Sponge Arenosclera brasiliensis

Haliclonacyclamine E, arenosclerin A, arenosclerin B, and arenosclerin C

P. aeruginosa and 10 methicillin-resistant S. aureus strains

d

[54]

Sponge Acanthostrongylophora species

12,34-Oxamanzamine E, 8-hydroxymanzamine J, and 6-hydroxymanzamine E

Mycobacterium tuberculosis

d

[58]

Micromonospora strain

Diazepinomicin (ECO-4601)

Certain gram-positive bacteria

d

[68]

Fugus Stachybotrys sp. MF347

Stachyin B

B. subtilis, S. epidermidis and methicillin-resistant S. aureus

d

[95]

Fungus Trichoderma sp. strain MF106

Trichodin A

B. subtilis and S. epidermidis

d

[96]

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Sponge Australian Axinella sp.

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Continued

Chemical Class

Source

Chlorinated benzophenone

Marine fungus strain CNL-365, Pestalotia sp.

Chlorinecontaining antibiotics

Phenazine antibiotic

Not provided (d).

Isolated Compound

Potential Target

Mode of Action

Reference

Pestalone

Methicillin-resistant S. aureus and vancomycin-resistant E. faecium

d

[71]

Fungus Aspergillus ostianus strain TUF 01F313

8-Chloro-9-hydroxy8,9-deoxyasperlactone, 9-chloro-8-hydroxy-8,9 deoxyasperlactone, and 9-chloro-8-hydroxy8,9-deoxyaspyrone

Ruegeria atlantica

d

[73]

Halophilic marine bacterium

LL-14I352a

E. coli

Disruption of cytoplasmic membrane and ability to restrict DNA synthesis

[97]

Novel Pseudomonas sp.

a-pyrone I

B. subtilis, S. aureus, M. catarrhalis, and E. faecium

Interruption of the cellular uptake of amino acids and acetates leading to the disruption of membrane

[98]

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TABLE 10.1 Summary of Antibiotics/Antibacterial Agents Derived From Marine Organismsdcont’d

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reef cod fillet, Epinephelus diacanthus was extended to greater than 21 d at 4 C upon spraying 2.0 mL of 1600 AU/mL bacteriocin on the latter compared to the short lifetime of the control (less than 14 d). Therefore, the bacteriocin PSY2 which was confirmed as a protein due to its inactivity against trypsin treatment acted as an antibiotic which could be utilized for the preservation of high-cost seafood [75]. A new compound designated as Hc-cathelicidin (Hc-CATH) comprising of 30 amino acids was the first cathelicidin to be isolated from the sea snake Hydrophis cyanocinctus. It was seen to exhibit powerful antimicrobial activities by dislocating the pathogen’s cell membrane thus killing the bacterial cells. Low cytotoxicity against mammalian cells was also observed making it a good candidate for further development as an antibiotic [76]. Crassostrea madrasensis, an edible oyster found in India, generated a protein with bacterial inhibitory capacities against various human pathogens namely Vibrio parahaemolyticus, Streptococcus sp., and Staphylococcus sp. in the agar well diffusion assay with minimum inhibitory concentration (MIC) being greater than 0.1 mL [77]. A new compound namely Myticusin-1 was isolated from hemolymph of adult mussels M. coruscus in Zhoushan, China. Myticusin-1 is an 11 kDa peptide (104 amino acids) including 10 cysteines forming five disulfide bonds, and 30 residues N terminal sequence, where its tertiary configuration was principally categorized by alpha-helixes. Myticusin-1 was proven to exhibit resilient antibacterial activities against gram-positive strains namely B. subtilis, S. aureus, Sarcina luteus, and Bacillus megaterium (MIC < 5 mM). A weaker effect was seen against gram-negative strains such as E. coli, V. parahaemolyticus, P. aeruginosa, and Vibrio harveyi (MIC > 10 mM). This compound was perceived to act on the cell wall of both S. luteus and E. coli where laminar mesosomes were seen to appear followed by cell wall effects including unevenness of its thickness as well as the separation of the cytoplasmic membrane from the cell wall [32]. Hormaomycin B and C (Fig. 10.1) from a marine mudflat-derived actinomycete strain (SNM55) were isolated from Mohang, Korea. Hormaomycin B and C were peptide-derived compounds with highly modified amino acid residues. The two cyclic depsipeptides possessed distinctive structural units, namely 4-(Z)-propenylproline, 3-(2-nitrocyclopropyl) alanine, 5-chloro1-hydroxypyrrol-2-carboxylic acid, and b-methylphenylalanine. Both were shown to possess substantial inhibitory properties against pathogenic bacterial strains Kocuria rhizophila NBRC 12,708 [69]. Another depsipeptide called etamycin (Fig. 10.1) was for the first time isolated from an actinomycete strain (CNS-575) from Nasese shoreline, Viti Levu, Fiji. The structure of etamycin was certified as a three distinct rotamer appearing in the 2D nuclear magnetic resonance spectrum. Etamycin, belonging to the streptogramin antibiotic class, was shown to have potential antibacterial activities against a range of clinically relevant hospital-associated

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R = H hormaomycin B R = CH3 hormaomycin C

etamycin

neamphamide B FIGURE 10.1 Structures of antibiotics in protein/polypeptide class.

and community-associated methicillin-resistant S. aureus (HA- and CA-MRSA) where the MIC was only 1e2 mg/L. In addition, gram-positive bacteria namely Streptococcus pyogenes and Streptococcus agalactiae as well as Gram-negative bacteria such as coccobacilli and Moraxella catarrhalis were also affected by etamycin which furthermore showed no cytotoxity even at 128 mg/L. Etamycin exhibited promising time-kill kinetics in comparison to

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vancomycin (another MRSA antibiotic) as well as exposed its ability to prevent death in a murine model of systemic lethal MRSA infection. Etamycin, alone, was seen to be prominent in the obstruction of protein synthesis in bacterial cells as compared to other streptogramin antibiotic [quinupristindalfopristin (Synercid): presently used in complex cutaneous infections] which are only able to act in pairs where quinupristin bind to 50S ribosomal subunit averting polypeptide elongation and dalfopristin enhance the latter’s activity by binding to another site on the 50S ribosomal subunit in order to inhibit protein synthesis [78]. Neamphamide B (Fig. 10.1), a cycle depsipeptide, was isolated from the marine sponge Neamphius sp. in Japan. Neamphamide B possessed antimycobacterial abilities against Mycobacterium smegmatis at MIC 1.56 mg/mL under both aerobic and hypoxic conditions. Furthermore, it was also proven active against Mycobacterium bovis Bacillus Calmette-Gue´rin (BCG) with MIC values 6.25e12.5 mg/Ml making it a good antimycobacterial agent [79]. A new cationic compound comprising of three positively charged amino acids (one histidine and two lysine) and one negatively charged amino acid (aspartic acid) having approximately 50% of hydrophobic amino acid content was designated as myxinidin. It was isolated from the acidic epidermal mucus of the hagfish M. glutinosa L. found in Canada. A wide range of pathogenic bacteria such as Salmonella enterica serovar Typhimurium C610, E. coli D31, Aeromonas salmonicida A449, Yersinia ruckeri 96-4, and Listonella anguillarum 02e11 was tested against myxinidin where the latter was highly dominant at the minimum bactericidal concentration 1.0e2.5 mg/mL. It was further noted that myxinidin was able to preserve its antibacterial capacities in elevated sodium chloride concentration (up to 0.3 M) as well as showed no hemolytic activities against mammalian blood cells. Myxinidin was also exposed to be 16 times stronger than pleurocidin NRC-17 (another antimicrobial peptide) against the tested pathogenic microorganisms [33]. Additional studies suggested that this type of compound had the ability to disrupt the cytoplasmic membrane [80] or the restriction of nucleic acid synthesis [81].

Polyketide/Macrolactones An actinobacterial strain SCSIO 01,127 from the Streptomyces genus isolated from sediment in the South China Sea was revealed to produce two new lobophorins analogs called lobophorin E and F (Fig. 10.2). Both compounds exhibited antibacterial activities against S. aureus ATCC 29,213, Enterococcus faecalis ATCC 29,212, and Bacillus thuringensis SCSIO BT01. It was noted that the MIC of these two compounds were 8 and 2 mg/mL, respectively, against B. thuringensis SCSIO BT01. Moreover, lobophorin F displayed better antibacterial activities against S. aureus ATCC 29,213 and E. faecalis ATCC 29,212 with the MIC being 8 mg/mL. It was also proven that the lack of hydroxyl group on C-32 could be beneficial in the enhancement of the antimicrobial features [70].

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FIGURE 10.2 Structures of antibiotics in polyketide/macrolactones class.

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The spirotetronate polyketide namely abyssomicin C (Fig. 10.2) which was isolated from marine Verrucosispora, had the ability to restrict the biosynthetic precursor of folic acid (vitamin B9) named para-aminobenzoic acid (pABA, 41). As a result, DNA synthesis was affected causing some kind of mutation and eventually lead to the cell’s detriment. This compound was proven to hinder development of methicillin-resistant S. aureus with its MIC being 5.2 mg/mL [67]. The bacteria B. subtilis MTCC 10,403 associated with the seaweed Anthophycus longifolius produced a novel antimicrobial metabolite labeled as 7-O-methyl-50 -hydroxy-30 -heptenoateemacrolactin which has a polyketide backbone. According to the agar diffusion method, 7-O-methyl-50 -hydroxy-30 heptenoateemacrolactin disclosed a diameter of 18 mm as the inhibitory zone against Aeromonas hydrophila and 16 mm against V. parahemolyticus ATCC 17,802 at a concentration of 100 mg on disk. Finally, due to its lipophilic characteristics, 7-O-methyl-50 -hydroxy-30 -heptenoateemacrolactin was seen to penetrate easily through the lipophilic membrane of the bacteria, henceforth exhibiting higher bactericidal capacities [82]. A novel Streptomyces sp. JRG-04 isolated from the mangrove sediment gave rise to an aromatic polyketide which was structurally related to aromatic benzoisochromanequinone polyketide antibiotic compound having good bioactivities against diverse bacteria. This new compound was found potent against both gram-positive and gram-negative bacteria where it had an MIC of 1.25e2.5 mg/mL against S. aureus MTCC 3160 compared to other antibiotic compounds like streptomycin with MIC values 1.5e2.5. An MIC of 5 mg/mL could disrupt the cell membrane of methicillin resistant S. aureus resulting in cell death as shown by staining their nucleic acid with both ethidium bromide (impermeable to membrane) and acridine orange (permeable to cell membrane). It was also noted that this novel compound had no cytotoxic effect on Cardiomyoblasts (H9C2) cell lines [83]. A low salinity mass culture broth of a marine Bacillus sp. 09ID194 yielded three original 24-membered macrolactones which are named macrolactin X, Y, and Z (Fig. 10.2). These three compounds exhibited antimicrobial activities against B. subtilis (KCTC 1021), E. coli (KCTC 1923), and Saccharomyces cerevisiae (KCTC 7913). It was also pointed out that in order to be more effective against pathogenic organisms, the hydroxyl group on C-15 in the macrolactone ring of the macrolactins boosted up the antibiotic activities [84]. Macrolactin S (Fig. 10.2), a 24-membered ring lactone, was isolated from a culture broth of marine Bacillus sp. which was obtained from the sea sediment of East China Sea. This one was perceived to possess 5 oxygenated methines, 12 olefinicmethines, 5 methylenes, a methyl and a lactone carbonyl carbon and it was the first macrolactin to be hydroxylated at C-12. This new compound was demonstrated to be a powerful antibacterial agent, which could act against E. coli, S. aureus, and B. subtilis at an MIC of 0.2, 0.7, and 100 mg/mL, respectively [85]. Lindgomycin and ascosetin (Fig. 10.2) were unusual

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polyketides isolated from mycelia and culture broth of two Lindgomycetaceae fungal strains KF970 and LF327 derived from association with a sponge in the Baltic Sea. Both compounds were seen to possess two distinct domains, a bicyclic hydrocarbon and a tetramic acid, linked by a bridging carbonyl. High inhibitory activities were displayed against B. subtilis and Staphylococcus epidermidis with IC50 (concentration causing 50% inhibition of the desired activity) values ranging from 2 to 6 mM. Moreover, strong antibiotic capacities were noted against methicillin-resistant S. aureus with IC50 values 5.1 (0.2) mM for Lindgomycin and 3.2 (0.4) mM for ascosetin [86]. Two new oxaphenalenone dimers talaromycesone A and B (Fig. 10.2) were isolated from the culture broth and mycelia of the marine fungus Talaromyces sp. strain LF458 obtained from tissues of the sponge A. verrucosa at a depth of 20 m. Talaromycesone A was seen to exhibit antibacterial activities against clinically relevant strains S. epidermidis and the methicillin-resistant S. aureus at IC50 value 3.70 (0.13) mM and 5.48 (0.03) mM, respectively, whereas talaromycesone B exhibited antibacterial capacities against the same pathogens at IC50 values 17.36 (0.05) mM and 19.50 (1.25) mM, respectively [74].

Anthroquinone Class Streptomyces cyaneofuscatus M-27 associated to seaweed (Phylum heterokontophyta) from the Central Cantabrian Sea were seen to produce cosmomycin B (Fig. 10.3). According to a study carried out previously by Li et al. [87], cosmomycin B isolated from a soil sample in Yunnan Province showed the ability to inhibit gram-positive bacteria as well as hinder DNA synthesis of P388 of leukemia cell in vitro with IC50 value 5.47 mg/mL. Aranciamycin I and J (Fig. 10.3) are two novel anthracycline antibiotics and aranciamycin A and aranciamycin, two known compounds were isolated from the Australian marine-derived Streptomyces sp. (CMB-M0150) in marine sediment. Aranciamycins were noted as different from other anthracycline compounds isolated from microorganisms due to the lack of an amino group on their sugar moiety. The four compounds were able to inhibit the growth of M. bovis BCG in vitro at MIC ranging from 10 to 30 mM and IC50 values varying from 0.7 to 1.7 mM as well as against B. subtilis strains at MIC ranging from 3.7 to 15 mM and IC50 values varying from 1.1 to 6.0 mM. Taking into consideration the low cytotoxicity of these isolated marine compounds, more work should be carried out on its mode of action for future development in the medical field [88]. Zafrin (Fig. 10.3), a new compound isolated from the marine bacterium Pseudomonas stutzeri derived from the intestinal tract of a Ribbon fish (Desmodema spp.), was revealed to be 4b-methyl-5, 6, 7, 8 tetrahydro-1 (4b-H)phenanthrenone. Zafrin was a stable uncharged metabolite being both hydrophobic and lipophilic and exhibited potent antibacterial activities against some

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FIGURE 10.3 Structures of antibiotics in anthroquinone class.

pathogens like S. aureus, and Salmonella typhi with MIC values for the gram-positive bacteria varying from 50 to 75 mg/mL to 75e125 mg/mL for gram-negative bacteria. Zafrin revealed a destructive effect on the cytoplasmic membrane of B. subtilis with a faster time kill kinetics compared to other antibiotics such as ampicillin, vancomycin, and tetracycline [89].

Polybrominated Biphenyl Class The marine bacteria Pseudoalteromonas phenolica sp. O BC30T were reported to produce a 3,30 ,5,50 -tetrabromo-2,20 -biphenyldiol (halogenated biphenyl compound) called MC21-A as illustrated in Fig. 10.4 which was considered as a symmetrical aromatic benzene. This new marine derived antibiotic with MIC of 1e2 mg/mL had the capacity to render the cell membranes of bacteria permeable, thus leading to cells death. Moreover, a concentration of up to

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FIGURE 10.4 Structures of antibiotics in polybrominated biphenyl class.

50 mg/mL demonstrated no cytotoxicity against human normal fibroblast, rat pheochromocytoma, and vero cells [90]. Another antibiotic called MC21-B (Fig. 10.4) has been isolated from the same marine bacterium P. phenolica O-BC30T. MC21-B was revealed to contain three bromines, a hydroxyl residue, aromatic benzene as well as halogens and was proven to be 2,20 ,3-tribromo-biphenyl-4-40 -dicarboxylic acid. MC21-B had potent antibacterial activity against 10 clinical isolates of MRSA which also showed MIC between 1 and 4 mg/mL. Moreover, MC21-B acted significantly against B. subtilis and Enterococcus serolicida. Gram-positive and gram-negative bacteria possessing contrasting cell wall structures suggested that the mode of action of this metabolite was related to the disruption of the cell membrane of the pathogens. When comparing MC21-B and MC21-A, it was also proposed that the number of bromines present in the structures might have an important role in the strength of antibacterial activity [91].

Terpenoid Class Terretonin G (Fig. 10.5), a sesterterpenoid, was isolated from the fungus Aspergillus sp. OPMF00272 from a porifera collected in Okinawa, Japan. An antimicrobial assay using paper disk revealed that Terretonin G exhibited antibiotic capacities against gram-positive bacteria S. aureus FDA209P, B. subtilis PCI219, and Micrococus luteus ATCC9341 with an inhibition zone of 10, 8, and 8 mm, respectively [72]. The Red Sea sponge named Prianos sp., residing at a depth of 30 m generated two compounds called prianicin A and B as seen in Fig. 10.5. Both had similar structures which were composed of a 6-membered ring cyclic peroxide, but the stereochemistry of the propionic acid side chain as well as the carbon skeleton were different. These two metabolites exhibited strong inhibition zone being 13 mm and >13 mm at MIC values 2.5 and 1.0 mg/mL, respectively, against beta hemolytic Streptococcus. Their actions were 4e10 times more efficient than tetracycline [92]. The strain CNQ-525 (Genus: tentatively called MAR4) resulting from the ocean sediments at 152 m deep in La Jolla, California produced three novel chlorine-containing terpenoid dihydroquinones (1e3; Fig. 10.5).

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FIGURE 10.5 Structures of antibiotics in terpenoid class.

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In all the three compounds isolated, the cyclohexane section’s structure and the presence of chlorotetrahydropyran ring were suggested to be the result of a halogen (“Clþ”) induced cyclization. The three isolated compounds associated to the napyradiomycins antibiotics class, expressed important antibacterial activities against MRSA, and vancomycin-resistant Enterococcus faecium (VREF). Compound 1 (3-chloro-10a-(3-chloro6-hydroxy-2,2,6-trimethylcyclohexylmethyl)-6,8-dihydroxy-2,2,7-trimethyl3,4,4a,10a-tetrahydro-2H-benzo[g]chromene-5,10-dione) was effective against MRSA and VREF with MIC values 1.95 and 3.90 mg/mL, respectively. Compound 3 (3-chloro-10a-(3-chloro-6-hydroxy-2,2,6trimethylcyclohexylmethyl)-6,8-dihydroxy-2,2,7-trimethyl-3,4,4a,10a-tetrahydro-2H-benzo[g]-chromene-5,10-dione) was active against MRSA and VREF with MIC values 1.95 mg/mL compared to compound 2 (3-chloro10a-(3-chloro-6-hydroxy-2,2,6-trimethylcyclohexylmethyl)-6,8-dihydroxy2,2,7-trimethyl-3,10adihydro-2H-benzo[g]chromene-5,10-dione) with MIC values 15.6 mg/mL against both MRSA and VREF [93]. Two novel compounds named sarcotrocheliol acetate and sarcotrocheliol as shown in Fig. 10.5 were isolated from the soft coral Sarcophyton trocheliophorum from the Red Sea, Saudi Arabia. These two metabolites were classified as pyrane-based cembranoids, which are considered as diterpenoids with 14-membered ring structures. Both compounds showed strong antibacterial activities against S. aureus, Acinetobacter spp., and MRSA with MIC varying from 1.53 to 4.34 mM with the inhibition zones’ diameter ranging from 12 to 18 mm [94]. Two novel diterpenes compounds named 10- and 15-formamido-kalihinol F were isolated from two Philippine Acanthella cavernosa marine sponge specimens. These antibiotics had the ability to inhibit bacterial folate (cofactor for metabolic processes) biosynthesis [95].

Alkaloid Class Stachyin B (Fig. 10.6), a new spirocyclic drimane coupled by two drimane fragment building blocks, was isolated from the fugus Stachybotrys sp. MF347. This novel compound was the first discovered spirocyclic drimane coupled by a spirodihydrobenzofuranlactam unit and a spirodihydroisobenzofuran unit where the linking point was an NeC bond. Stachyin B was seen to inhibit various gram-positive bacteria namely B. subtilis [IC50: 1.42 (0.07)] mM, S. epidermidis [IC50: 1.02 (0.09)] mM, and the MRSA [IC50: 1.75 (0.09)] mM. The low cytotoxic activities of this novel compound for the mouse fibroblasts cell line NIH-3T3 and the carcinoma cell line HepG2 were at IC50 values 13.01 (0.46) mM and 14.27 (1.54) mM, respectively [96]. Trichodin A (Fig. 10.6), being an unusual pyridine, was acquired from the marine fungus Trichoderma sp. strain MF106 obtained from the Greenland Seas. Trichodin A was categorized as intramolecular cyclization of a pyridine

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FIGURE 10.6 Structures of antibiotics in alkaloid class.

basic backbone with a phenyl group. Gram-positive B. subtilis and S. epidermidis were successfully inhibited by this new compound at IC50 values 27.05  0.53 mM and 24.28  3.90 mM, respectively [97]. The marine sponge A. brasiliensis produced four novel tetracyclic alkylpiperidine alkaloids called arenosclerin A, arenosclerin B, arenosclerin C, and haliclonacyclamine E as demonstrated in Fig. 10.6. Arenosclerin A, arenosclerin C, and haliclonacyclamine E displayed antimicrobial activities against 11 hospital acquired antibiotic-resistant bacteria (a P. aeruginosa and 10 MRSA strains) as well as S. aureus ATCC 6538 with the inhibition zone

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ranging from 7 to 13 mm. However, arenosclerin B was seen to act only against 5 microbes namely S. aureus, P. aeruginosa, and three antibioticresistant S. aureus strains. The four alkaloids compounds proved to be cytotoxic against HL-60 (Leukemia), L929 (fibrosarcoma), B16 (melanoma), and U138 (colon) cancer cell lines at a range of 1.5e7.1 mg/mL [54]. A new substance called petrosamine B (a pyridoacridine alkaloid), isolated from the sponge Oceanapia sp. had the ability to inhibit the enzyme aspartate semialdehyde dehydrogenase needed for protein synthesis in the bacteria Helicobacter pylori at IC50 35 mg/mL [57]. A marine actinomycete of the genus Micromonospora (strain DPJ12) isolated from the marine ascidian D. proliferum in Japan produced a new dibenzodiazepine alkaloid named diazepinomicin (Fig. 10.6) which consisted of a dibenzodiazepine core connected to a farnesyl side chain. Antimicrobial activities were eminent against certain gram-positive bacteria with MIC around 32 mg/mL [68].

MODE OF ACTION The researches carried out about the detailed mode of action of marine antibiotics are scarce. However, this section will provide some of the specific targets of marine antibiotics and their related ways of actions.

Disruption of Membrane Leading to Restriction of DNA Synthesis A culture LL-141,352, isolated from a tunicate collected from the Pacific Ocean was identified as a halophilic marine bacterium. According to the biochemical induction assay, a new phenazine antibiotic LL-14I352a shown in Fig. 10.7 was revealed to possess antibacterial activities. LL-14I352a which contain an amino acid residue had the tendency to ease its transport through cytoplasmic membrane of the pathogens. LL-14I352a showed strong antibacterial activities against E. coli with an imp outer membrane mutation (MIC/MBC, 0.5/2 mg/mL) compared to the unchanged E. coli type. Moreover, this compound showed its ability to restrict DNA synthesis by 82% (IC50: 0.10 mL/mL) obtained from the

FIGURE 10.7 Structures of LL-14I352a and a-pyrone I.

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measurement of radiolabeled precursors 3H-Tdr, 3H-Udr, and 3H-AA into trichloroacetic acid (TCA)-precipitable material from E. coli imp cultures [98]. A novel species of Pseudomonas was isolated from the culture F92S91 obtained from a marine sponge in Fiji generated a new a-pyrone I (Fig. 10.7). The strain B. subtilis was manipulated to acquire a lacZ reporter gene fused with cerulenin and triclosan-responsive promoter which had the capacity to detect fatty acid biosynthesis enzymes inhibitors. a-Pyrone I revealed the highest antibacterial activities against B. subtilis (MIC: 1 mg/mL) and S. aureus, M. catarrhalis, and E. faecium with MIC values ranging from 2 to 4 mg/mL. a-Pyrone I was seen to interrupt the cellular uptake of amino acids and acetates leading to the disruption of membrane of B. subtilis. Cellular uptake of radiolabeled precursors for DNA, RNA, and protein were noted to be inhibited upon exposure of a-pyrone I [99].

Inhibition of Bacterial RNA Polymerase Salinamide A (SalA), as seen in Fig. 10.8, generated by the marine Streptomyces sp. CNB-091 isolated from the jellyfish Cassiopeia xamachana is considered as a bicyclic depsipeptide antibiotic which is comprised of seven amino acids residues and two nonamino acid residues. SalA had the expertise of inhibiting the RNA polymerase active-center function allosterically through conformational changes. SalA target overlapped with a “bridge helix cap” which in turn is divided into three subregions namely the “bridge-helix N-terminal hinge” (BH-HN), the “F-loop,” and the “link region.” More precisely, the RNA polymerase active-center function could be hindered by SalA where the proposed BH-HN hinge-opening and hinge-closing was repressed affecting RNA chain construction. By carrying out macromolecular synthesis assay by observing the integration of [14C]-uracil into RNA demonstrated RNA synthesis inhibition upon addition of SalA in a bacterial culture. Consequently, SalA restricted addition of nucleotide in transcription initiation and elongation. Potent antibacterial activities were noted against gram-negative bacteria such as Enterobacter cloacae ATCC 13,047 and Haemophilus influenza ATCC 49,247 with MIC 1.56 and 6.25 mg/mL, respectively [100]. A new depsipeptide analog named salinamide F (Fig. 10.8) was also isolated from the same marine-derived Streptomyces sp., strain CNB-091 which showed potential ability to constrain bacterial RNA polymerase. The inhibitory activity of Salinamide F was detected by the fluorescencedetected RNAP-inhibition assay. This compound had the same mode of action on bacterial RNA polymerase as SalA where it showed IC50 of 4 mM against S. aureus RNAP and 2 mM for E. coli RNAP. Significant antibacterial effects were also seen against E. faecalis, H. influenza, Neisseria gonorrhoeae, E. cloacae with MIC50 values 12.5, 100, 12.5, 25, and 50 mg/mL, respectively [101].

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FIGURE 10.8 Structures of salinamide A and F.

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Quorum Sensing Manipulation/Inhibition The microbial world is a vast environment where each bacterium plays a unique role by producing, sensing, or reacting to a diversity of chemical signals [102]. Bacteria had developed advanced strategies due to the so-called intracellular and intercellular communication which is usually controlled by quorum sensing (QS). In other words, QS can engender chemical signal which in turn can regulate gene expression depending on the cell-population density [103]. QS is utilized by gram-positive as well as gram-negative bacteria in order to control a great number of physiological events like virulence, antibiotic production, biofilm formation, competence, as well as sporulation [103e106]. Thus, in order to interfere with signals promoting virulence and biofilm formation in pathogenic microorganisms, QS should be mastered and thus enable scientist to identify signals which could boost up antibiotic production against pathogens. For example, according to a previous study, the detrimental effect of P. aeruginosa (involved in cystic fibrosis) was altered by another microorganism being Candida albicans (reside in body cavities). In general, P. aeruginosa has the capability to kill C. albicans by sticking to its surface and execute the cells. However, in order to protect itself, C. albicans changed its shape into filamentous cells which is activated by a bacterial signal 3-0-C12 homoserine lactone (30C12HSL), one of two P. aeruginosa quorum signaling compounds [101]. Therefore, this showed that interspecies communication has the aptitude to control signals in favor or in detriment of different pathogenic microorganisms. Another study carried out by Hentzer et al. showed the possibility of in situ exposure of N-acyl homoserine lactone (AHL)-mediated QS in P. aeruginosa biofilms. According to the secondary metabolite obtained from the Australian macroalgae Delisea pulchra, a halogenated furanone compound was synthesized. This new compound was seen to obstruct with P. aeruginosa cell-to-cell communication thus decreasing QS-controlled gene expression. In other words, the halogenated furanone could infiltrate microcolonies and halter cell signaling and QS in biofilm cells. Affecting the virulence of P. aeruginosa by interfering with biofilm formation showed another prospect for antibacterial activity [107]. An antibiotic malyngolide (MAL) isolated from the cyanobacterium Lyngbya majuscule in the Indian River Lagoon, USA, showed QS inhibition properties. It was seen that MAL-restricted responses of N-AHL reporters (more precisely LasR reporters) of P. aeruginosa at concentrations varying from 3.57 to 57 mM. Moreover, this QS inhibitor repressed elastase (enzyme able to breakdown protein) production (EC50: 10.6  1.8 mM) thus showed capacity to govern heterotrophic bacterial interactions [108].

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OPINION AND CONCLUSION For a long time, antibiotics have been on the primary bench in combatting bacterial infections. However, due to resistance and evolution of pathogens, antibacterial agents lost their effectiveness and power. For example, S. aureus, a pathogenic microorganism causing pneumonia or deep abscesses [109e111], has become methicillin-resistant and is tagged as “superbug.” As a matter of fact, many more harmful bacteria are following this path leading to increased threat for the entire universe. Study on the isolation of antibacterial compounds, their mechanisms of action as well as their biosynthetic pathway have been neglected for so long and now its on the urge to find new solutions to the aggravating problems of infectious diseases. The ocean is a treasure of cure for infectious diseases and only awaits to be discovered. Microorganisms thriving in extreme conditions such as the hydrothermal vents, arctic regions, or highly saline conditions have the capacity to generate unique and promising compounds which needs to be unveiled by advanced and innovative techniques of isolation and culturing. Moreover, selective, planned methodologies should be developed to be able to culture the unculturable microorganisms by carefully designing special, suitable, original media, and optimized laboratory conditions. Culturing the unculturable should also integrate the aspect of coculture which might play a vital role in activating dormant gene clusters, thus giving access to the encrypted, hidden organisms. Different techniques should be developed about triggering and challenging the organisms to produce highly active, intriguing, and valuable metabolites. Such techniques could be “metal-stress” methods or variation in the type of media used. The “metal-stress” strategy refers to the addition of different concentrations of heavy metals such as Cobalt, Zinc, or Nickel to name a few, to the microorganisms’ culture which showed the ability of activating dormant gene clusters as shown in a previous study carried out by Ding et al. [112]. Strains can also be engineered using the latest techniques of genomics, advanced biotechnology, metagenomics, and proteomics. New branches of science especially the chemical techniques should be integrated into the research of new potent antibiotics from the ocean such as mass spectroscopy, nuclear magnetic resonance, and diverse Chromatography techniques. Additional barrier restraining proper understanding of the real origin of the target metabolite is the wrong interpretation in symbiotic systems. As a step forward to be able to master the links between symbionts, host, and the environment, cutting-edge molecular techniques including the application of fluorescent probes along with classical methods should be applied to disclose the real heroes producing the lead compounds in the complex marine environment. Another important point to take into consideration is the understanding of the true role of antibiotics in nature. Antibiotics were only seen as weapons generated by microorganisms until recently new hypothesis have been put

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forward about their genuine role in nature as signaling agents for proper communication and stable environments. Decrypting the mystery of the exact function of antibiotics in its natural environment will be a first victory against the threatening rise of infectious disease. By decoding this secret, we might be able to discover other molecules which have the ability to boost up the power of antibiotics, thus making them more tenacious and efficacious against the most resistant pathogens. Studying the reason behind the resistance of microbes against antibiotics is another essential aspect, and it should be emphasized that the discovery of new antibacterial agents is not the only important point, but its further and continuous development in order to reach clinical trials is equally vital to achieve progress in combatting diseases caused by pathogens. It should also be pointed out that the relationship between antibiotics and the host, either humans or animals, must be meticulously scrutinized in order to improve its effectiveness and accuracy. The key to success of concretizing all of the above into reality needs the collaboration of scientists, government, as well as industries worldwide. From this chapter, it can be concluded that the ocean may be the sole defender of humanity against infectious diseases.

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