Antibiotics Development and the Potentials of Marine-Derived Compounds to Stem the Tide of Multidrug-Resistant Pathogenic Bacteria, Fungi, and Protozoa

As the search for new antibiotics continues, the resistance to known antimicrobial compounds continues to increase. Many researchers around the world, in response to antibiotics resistance, have continued to search for new antimicrobial compounds in different ecological niches such as the marine environment. Marine habitats are one of the known and promising sources for bioactive compounds with antimicrobial potentials against currently drug-resistant strains of pathogenic microorganisms. For more than a decade, numerous antimicrobial compounds have been discovered from marine environments, with many more antimicrobials still being discovered every year. So far, only very few compounds are in preclinical and clinical trials. Research in marine natural products has resulted in the isolation and identification of numerous diverse and novel chemical compounds with potency against even drug-resistant pathogens. Some of these compounds, which mainly came from marine bacteria and fungi, have been classified into alkaloids, lactones, phenols, quinones, tannins, terpenes, glycosides, halogenated, polyketides, xanthones, macrocycles, peptides, and fatty acids. All these are geared towards discovering and isolating unique compounds with therapeutic potential, especially against multidrug-resistant pathogenic microorganisms. In this review, we tried to summarize published articles from 2015 to 2019 on antimicrobial compounds isolated from marine sources, including some of their chemical structures and tests performed against drug-resistant pathogens.


Introduction
Antibiotics are a subcategory of that large group of chemical substances produced by microorganisms or made synthetically which include compounds that can inhibit the growth and even kill bacteria and other microorganisms in low concentration. Antimicrobials are the large group of chemical substances produced through natural (microorganisms, plants, and animals), semisynthetic or synthetic means and are effective against any microorganism (bacteria, fungi, virus, and parasite). These terms are used interchangeably today [1]. In 1929, the history of antibiotics began with the discovery of penicillin by Alexander Fleming and since then more antibiotics have been identified and some have been put to use. For more than six decades, antibiotics have remained unbeaten in their control of pathogenic disease-causing agents [2]. While some researchers continue to modify the existing antibiotics, more studies are focused on the discovery of new or novel antibiotics. The discovery and development of antibiotics with novel structural classes are very essential for some reasons. The resistance of microorganisms to available antimicrobials is on the increase, as is the toxic nature of some of currently available drugs, which limits their use. This is a serious threat to effective disease prevention and treatment of an ever-increasing range of infections caused by microorganisms including bacteria, parasites, viruses, and fungi [3,4].
Antimicrobial resistant pathogens are found in every country and we are fast running out of treatment options. This led WHO in 2017 to release a list of antibiotic-resistant "priority pathogens" that globally pose the greatest threat to human health ( Table 1). The aim of publishing this list is to guide and promote research and development of novel antibiotics. The list is made up of a catalogue of 12 families of bacteria which WHO divided into three categories according to the urgency of the need for new antibiotics: critical, high, and medium priority (https://www.who.int/news-room/detail /27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed). Other serious drug-resistant pathogens deliberately not included in the priority list are multidrug-resistant (MDR) or extensively drug-resistant (EDR) Mycobacterium tuberculosis, P. falciparum malaria, MDR Candida species (resistant to fluconazole, echinocandin, and amphotericin B), etc. This is because some of these pathogens such as M. tuberculosis are already a globally established priority for which innovative new treatments are also urgently needed [5,6].  Figure 1. Flow chart of phases used to identify articles included in this review. Some of these articles were got using (marine (NOT military) OR marine natural products OR marine-derived) AND ((invertebrate OR sponge OR coral OR cnidarian OR arthropods OR echinoderms OR tunicates OR algae OR bryozoan)-associated (bacteria OR fungi OR algae))) ((drug-resistant OR multidrugresistant) (bacteria OR fungi OR protozoa)) and careful insertion of (antibacterial OR antifungal OR antiprotozoal) and (oceans OR seas OR marshes OR bays OR shoreline OR estuaries OR deep sea OR coral reef OR coastal OR mangroves). Flow chart of phases used to identify articles included in this review. Some of these articles were got using (marine (NOT military) OR marine natural products OR marine-derived) AND ((invertebrate OR sponge OR coral OR cnidarian OR arthropods OR echinoderms OR tunicates OR algae OR bryozoan)-associated (bacteria OR fungi OR algae))) ((drug-resistant OR multidrug-resistant) (bacteria OR fungi OR protozoa)) and careful insertion of (antibacterial OR antifungal OR antiprotozoal) and (oceans OR seas OR marshes OR bays OR shoreline OR estuaries OR deep sea OR coral reef OR coastal OR mangroves).

Marine Ecosystem as a Source of Antibiotics
It is now obvious that the biological diversity of the ocean environment offers great promise as a source of antimicrobials for the future and could be potent against drug-resistant microbes, the "superbugs". There are more than two hundred thousand described species of algae and invertebrates in the ocean, and representatives of every phylum (marine organisms are exclusively the twelve phyla) are found in the sea. Only a small percentage of the total number of species living in these habitats have been discovered and described [11,12]. The bacteria in the oceanic subsurface are believed to be up to ten percent of the total living biomass carbon in the biosphere. An appreciable number of chemical compounds from some of these species have been isolated but only a few of these compounds have been evaluated in clinically relevant bioassays. These diverse chemical compounds are used by the microorganisms mainly for defence and not basically for metabolic processes, and they confer some evolutionary advantage to them. These novel chemicals with pharmaceutical potential are being sourced from bacteria, fungi, invertebrate-associated microbes, algae, sponge, coral, cnidarian, arthropods, echinoderms, fishes, crabs, ascidians, molluscs, and bryozoan. Researchers are exploring different oceanic environments with different temperatures, tides, salt concentration, and depth [13,14].
Research in marine natural products has resulted in the isolation and identification of numerous diverse, as well as novel, chemical compounds with potent pharmaceutical importance. Some of these compounds have been classified into alkaloids, lactones, phenols, quinones, tannins, terpenes, glycosides, halogenated, polyketides, xanthones, macrocycles, peptides, and fatty acids [13,14]. All these are geared towards discovering and isolating unique compounds with therapeutic potential.
The fermentation broth fraction of Streptomyces sp. SCA29 (India) had antibacterial activity against test bacterial pathogens, including MRSA ATCC NR-46171, and had other properties such as enzyme inhibitory and cytotoxic potentials. The spectral analyses led to the identification of an acetamide derivative, 4-methoxyacetanilide, as the bioactive compound [41]. An investigation by Yang et al. to discover novel antibiotics against multidrug-resistant pathogen led to the isolation of S. lusitanus OUCT16-27 from Indian Ocean (4495 m depth), which produced new angucycline, new grincamycin L (1), and other known compounds (Figure 2A). Only two compounds (1 and 2) exhibited moderate growth inhibitions against MDR pathogens tested (Table 3) [42]. Anti-MDR and anti-ESBL potential has been shown by the compounds produced by Streptomyces sp. Al-Dhabi-90 (Dammam, Saudi Arabia), which had an inhibitory effect against some pathogens and the chemical analysis of the broth revealed the presence of some compounds (Table 3) ( Figure 2B) [43].
Recently, da Silva et al. isolated an obligate marine actinomycete, Salinispora arenicola (Brazilian Atlantic Ocean), and from the fermentation broth of the bacterium they identified salinaphthoquinones ( Figure 2C), some of which had inhibitory activity against test drug-resistant pathogens (Table 3) [44].
A rare actinobacterial isolate, Nocardiopsis sp. strain SCA21 (Havelock Island, Andaman and Nicobar Islands, India), produced bioactive compounds ( Figure 2E), which exhibited broad spectrum inhibitory activity against MRSA strains as shown in Table 3 [47]. The fermentation broth fraction of Streptomyces sp. SCA29 (India) had antibacterial activity against test bacterial pathogens, including MRSA ATCC NR-46171, and had other properties such as enzyme inhibitory and cytotoxic potentials. The spectral analyses led to the identification of an acetamide derivative, 4-methoxyacetanilide, as the bioactive compound [41]. An investigation by Yang et al. to discover novel antibiotics against multidrug-resistant pathogen led to the isolation of S. lusitanus OUCT16-27 from Indian Ocean (4495 m depth), which produced new angucycline, new grincamycin L (1), and other known compounds (Figure 2A). Only two compounds (1 and 2) exhibited moderate growth inhibitions against MDR pathogens tested (Table 3) [42]. Anti-MDR and anti-ESBL potential has been shown by the compounds produced by Streptomyces sp. Al-Dhabi-90 (Dammam, Saudi Arabia), which had an inhibitory effect against some pathogens and the chemical analysis of the broth revealed the presence of some compounds (Table 3) ( Figure 2B) [43].
Recently, da Silva et al. isolated an obligate marine actinomycete, Salinispora arenicola (Brazilian Atlantic Ocean), and from the fermentation broth of the bacterium they identified salinaphthoquinones ( Figure 2C), some of which had inhibitory activity against test drug-resistant pathogens (Table 3) [44].
An actinobacterial strain identified as Kocuria marina CMG S2 associated with a brown macroalgae (Pelvetia canaliculata) (Karachi, Pakistan) was reported to produce a novel and potent antibiotic, kocumarin, which inhibited the growth of fungi and pathogenic bacteria, such as MDR bacteria strains of MRSA ATCC 33591, S. pyogenes, S. typhi, and P. aeruginosa at MIC of 10 µg/mL. This potency against MDR bacterial strains makes this antibiotic a good candidate for in vivo and other further studies [53]. Endophytic actinomycete, Nocardiopsis sp. GRG 2 (KT 235641), associated with macro algae (India), exhibited excellent anti-MDR and anti-ESBL activity pathogens, such as strains of MDR ESBL P. aeruginosa and K. pneumonia at MIC of 75 µg/mL. Based on chemical analysis, the fraction with anti-ESBL metabolites (Fraction 3) was confirmed to contain metabolite, named as 1, 4-diaza-2, 5-dioxo-3-isobutyl bicyclo[4.3.0]nonane (DDIBN) [54].
Recently, a potent antibiotic-producing strain of actinomycete, S. althioticus MSM3 isolated from marine intertidal macroalgae (Ulva sp.) (Cantabrian Sea in Pedreña, Cantabria) led to the isolation of desertomycin G ( Figure 3A), an antibiotic that possesses both antimicrobial and cytotoxic potentials. It inhibited the growth of MDR microorganisms in low concentration, as shown in Table 3. With these reported properties, desertomycin G will be a good candidate for further research, especially against drug-resistant pathogenic M. tuberculosis [55].

Marine/Mangrove Plant-Associated Bacteria
Streptomyces sp JRG-04 (Tamil Nadu, India), which previously had potent antimicrobial activity at low MIC level concentration against various pathogens, including MRSA, produced benzoisochromanequinones polyketides that had a toxic effect on MRSA cell membrane and increased the number of dead MRSA cells [56]. These therapeutic properties make this strain a good candidate for various pharmaceutical applications.

Invertebrate-Associated Bacteria (Sponge, Ascidian)
Streptomyces sp. LS298 (South China Sea) produced new cyclic dipeptide and echinomyci analogue which showed good inhibitory activity against drug-resistant pathogens ( Table 2) [57]. An ascidianassociated Streptomyces sp. strain CA-271078 (SaoTome), produced in addition to other compounds, a new napyradiomycin (MDN-0170) ( Table 2) which unlike others was not active against MRSA MB5393 at the highest concentration tested (> 64 µg/mL) [58]. In a co-culture experiment designed to induce production of antibacterial metabolites, Streptomyces sp. strain PTY087I2 associated with brown Panamanian tunicate (Styela canopus) from mangrove roots was co-cultured with other pathogens, especially MRSA, resulting strongly in enhanced antimicrobial activity against the test pathogens. The chemical analysis showed the presence of naphthoquinone derivatives, granaticin, granatomycin D, and dihydrogranaticin B [59].
Invertebrate-associated bacteria are very promising in the search for new antimicrobial compounds. The ethyl acetate crude extracts from liquid fermentation of tunicates-associated Gram-negative marine bacterium, Pseudoalteromonas rubra TKJD 22 (Indonesia) exhibited anti-MDR activity against some pathogens, including MDR E. coli and MDR-ESBL E. coli. The active compound in the fraction was identified to be a red-orange crystalline solid, isatin ( Figure 3B) [69]. Streptomyces sp. G248 from marine Sponge (Halichondria panicea) (East Vietnam Sea) produced new antimicrobial lavandulylated flavonoids (1-3) and other known compounds (4-10). Only the new compounds (1-3) inhibited the growth of MDR C. albicans 10231 (Table 3) and other test microorganisms [70].

Fungi from Marine Sediments
Wang et al. isolated two new benzoate derivatives, one new phenylacetate derivative and another known compound from Engyodontium album (at 2530 m in the Pacific Ocean). Only compound 3, ethyl 3,5-dimethoxy-2-propionylphenylacetate, had an inhibitory effect on MRSA ATCC 43300 at a MIC value of 7.8 µg/mL [71].
New compounds with anti-MRSA activity, according to Suga et al, named paraphaeosphaeride D (1) and berkleasmin F (2) together with known compound, berkleasmin A (3), were isolated from an artificial pond sediment fungus belonging to the Didymosphaeriaceae family, Paraphaeosphaeria sp. TR-022 (Machida city, Tokyo). This is in addition to their previously isolated fungal metabolites (biverlactones, aranorosin, and aogacillins). These compounds (1-3) not only enhanced anti-MRSA activity of Arbekacin (ABK) but also inhibited the growth of ABK-resistant MRSA TH-1466 and another 26 clinical ABK-resistant MRSA strains at MIC value range of 15.7-256 µg/mL [72].
To show that standard laboratory cultures can hinder activation of specific gene clusters, which in turn hinder the production of metabolites with novel properties, Auckloo and his group's addition of heavy metal cobalt (6 mM) to culture broth, in the form of "metal stress", induced the production of new polyketides (bearing a migrated polyene chain) ( Table 2). These three compounds derived from Penicillium sp. BB1122 (Zhoushan coast, China) inhibited the growth of MRSA at low concentrations [74]. Samples collected from Bohai Sea, China, led Xu et al. to isolate a diphenyl ethers-producing Aspergillus ochraceus LCJ11-102 sp. strain CUGB-F046. These compounds, diorcinol K (1), diorcinol D (2), diorcinol F (3), and diorcinol I (4), exhibited antibacterial activity against test pathogens including MRSA ATCC 700698 at MICs of 3.125, 6.25, > 50, and 6.25 µg/mL, respectively [75].
Six new diketopiperazines (1-3) and another known four compounds were isolated from the fermentation broth culture of the fungus, A. versicolor MF180151 (Bohai Sea, China). These compounds showed some levels of biological activity and only versicolorin B (5) and averufin (6) had inhibitory activity against MRSA [79].
In addition to five known compounds produced by Penicillium sp. IMB17-046 (China mangrove swamp), new compounds ( Figure S1) were identified, which had a broad-spectrum of antiviral and antibacterial activities. Only compounds 1 and 2 had inhibitory activity against drug-resistant H. pylori 159 at MIC values of 16 and 1 µg/mL, respectively [82]. Another anti-drug resistant metabolite ( Figure 3C), inhibited MDR H. pylori as shown in Table 3. These compounds were produced by coastal sediment-derived Trichoderma atroviride strain KNUP001. Besides, the compounds showed some other interesting biological activities, which makes it a candidate for further in vivo animal model experiments [7].

Marine Alga-Associated Fungi
The Mediterranean Sea green alga, Flabellia petiolata, sampled at Elba Island, harboured two fungal strains, including Microascacea sp. strain MUT 4861 and Beauveria bassiana strain MUT 4865. These researchers identified the components of the crude extracts of these fungal strains to be made up of several sphingosine bases, which may be responsible for their broad spectrum of antibacterial activity against MDR pathogens (Table S1) [6].

Marine Plant-Associated Fungi
P. sclerotiorum M-22 from rotted leaf (Hainan province, China) synthesized azaphilone compounds, penicilazaphilone B and C. These compounds exhibited potent biological activities, including the inhibition of ESBL K. pneumoniae ATCC 700603 by Compound B and C at MIC values of 500 and 15.63 µg/mL, respectively [87]. An endophytic fungus of Nymphaea nouchali (Sri Lanka) called Chaetomium globosum, led to the isolation of cytochalasans, chaetoglobosin A and C from the crude extract of the two distinct fungi. The compounds showed antibacterial activities against test microorganisms, and chaetoglobosin A (1) inhibited MRSA ATCC 33591 and S. aureus ATCC 43300 at MIC values of 32 and 32 µg/mL, respectively [88].
The rhizosphere has been a dynamic region governed by complex interactions between microorganisms and plants. The pattern and composition of root exudates affected microbial activity and population numbers. Chen et al. isolated mangrove rhizosphere soil-derived fungus, Penicillium janthinellum HK1-6 (Hainan Island, China), that produced new azaphilones, penicilones A−D (1−4), from which other compounds (parental azaphilones, E (5) and F (6)) were derived through ester hydrolysis of compounds 2 and 4. As an anti-MRSA, MRSA ATCC 43300, MRSA ATCC 33591, and VR E. faecalis ATCC 51299 were inhibited by compounds 2-4 at a MIC value range of 3.13-6.25 µg/mL [90].
Taeniolella sp. BCC31839 isolated from a wood (family Poaceae) in a mangrove forest, Bangkok, Thailand, synthesized two unknown enantiomeric chromone derivatives, and another 6 known compounds. These two novel compounds (R)-and (S)-taeniolin (1 and 2) exhibited no inhibitory activity against MDR P. falciparum but lateropyrone (3) inhibited the same malaria parasite at a MIC value of 9.75 μ/mL [98]. Taeniolella sp. BCC31839 isolated from a wood (family Poaceae) in a mangrove forest, Bangkok, Thailand, synthesized two unknown enantiomeric chromone derivatives, and another 6 known compounds. These two novel compounds (R)-and (S)-taeniolin (1 and 2) exhibited no inhibitory activity against MDR P. falciparum but lateropyrone (3) inhibited the same malaria parasite at a MIC value of 9.75 µ/mL [98].

Invertebrate-Associated Fungi (Sponges, Ascidians, Crab)
Antibacterial compounds talaromycesone A and B (oxaphenalenone dimers), produced by a sponge (Axinella verrucosa)-associated fungus, Talaromyces sp. strain LF458, was collected at the Mediterranean Sea (Italy). The compounds were active against pathogens, including MRSA at IC 50 of 4.6 µM [99]. Two marine fungal strains (LF327 and KF970) in the family Lindgomycetaceae that produced an unusual polyketide were isolated from a sponge (Halichondria panicea) of the Baltic Sea (Kiel Fjord) and the Antarctic. The new polyketides, lindgomycin (1) and ascosetin (2), possess an unusual carbon skeleton, such that the bicyclic hydrocarbon and a tetramic acid (two distinct domains) are joined by a bridging carbonyl. These compound exhibited antimicrobial activity against MRSA at MIC values of 5.1 ± 0.2 and 3.2 ± 0.4 µM [1].
Atlantic sponge (Grantia compressa)-associated fungus, Eurotium chevalieri MUT 2316 (West Coast of Ireland), produced 10 metabolites with promising antibacterial (Table 3) ( Figure 4A) as well as antiviral activities [106]. This study demonstrated and reaffirmed that "One strain, many compounds" (OSMAC) is a powerful method to stimulate and enhance the production of an incredible variety of new secondary metabolites.
The rice culture of A. niger from marine sponge (Haliclona sp) tissues produced new 4-hydroxy-αpyrones (nipyrones A-C (1-3)) and a known analogue, germicidin C (4). These compounds, which differ in their functional group substitution and side chain length, exhibited weak to moderate antimicrobial activities with MRSA [107].
An antimicrobial dolabellanes and atranones produced by the toxigenic fungus, Stachybotrys chartarum TJ403-SS6, synthesized three new dolabellane-type diterpenoids and three new atranones. Compound 2 is structurally related to Compound 3 due to the presence of a 1, 14-seco dolabellanetype diterpenoid skeleton. Additionally, compound 4 is the first C23 atranone having a propan-2-one motif linked to a dolabellane-type diterpenoid by a carbon−carbon bond; and compound 5 represents the first example of a C24 atranone with a 2-methyltetrahydrofuran-3-carboxylate motif fused to a dolabellane-type diterpenoid at C-5−C-6. Compound 4 ( Figure 4B) showed inhibitory activity against only MRSA ATCC 43300 and C. albicans ATCC 10231 (Table 3), while other pathogens were not inhibited by all the compounds [110].
A wild crab (Pachygrapsus crassipes) associated Penicillium sp. ZZ380 produced penicipyrroether A in a PDB medium and pyrrospirone J in a BMPM medium, and other known compounds (3-6, 9 and 10) ( Figure S2). Aside from other biological activities, the penicipyrrodiether A, which is a cyclocondensation product of GKK1032 analogue via the addition of a five-membered ether ring, showed inhibitory activity at MIC value of 5.0 μg/mL against MRSA ATCC 43300, and had anti-glioma proliferation activity [111] while pyrrospirone J inhibited MRSA at a MIC value of 1.7 μg/mL [112].
The co-culture of a staghorn Gorgonian fungus, Rhinocladiella similis 35, from Luhuitou fringing reefs and actinomycete, S. rochei MB037 (South China Sea) resulted in isolation and identification of new fatty acids with rare nitrile group, a new chromone derivative,) and another two known 18membered macrolides ( Table 2). Only compound 1 exhibited anti-MRSA activity against MRSA at MIC value of 0.195 μg/mL [113].  An antimicrobial dolabellanes and atranones produced by the toxigenic fungus, Stachybotrys chartarum TJ403-SS6, synthesized three new dolabellane-type diterpenoids and three new atranones. Compound 2 is structurally related to Compound 3 due to the presence of a 1, 14-seco dolabellane-type diterpenoid skeleton. Additionally, compound 4 is the first C 23 atranone having a propan-2-one motif linked to a dolabellane-type diterpenoid by a carbon−carbon bond; and compound 5 represents the first example of a C 24 atranone with a 2-methyltetrahydrofuran-3-carboxylate motif fused to a dolabellane-type diterpenoid at C-5−C-6. Compound 4 ( Figure 4B) showed inhibitory activity against only MRSA ATCC 43300 and C. albicans ATCC 10231 (Table 3), while other pathogens were not inhibited by all the compounds [110].
A wild crab (Pachygrapsus crassipes) associated Penicillium sp. ZZ380 produced penicipyrroether A in a PDB medium and pyrrospirone J in a BMPM medium, and other known compounds (3-6, 9 and 10) ( Figure S2). Aside from other biological activities, the penicipyrrodiether A, which is a cyclo-condensation product of GKK1032 analogue via the addition of a five-membered ether ring, showed inhibitory activity at MIC value of 5.0 µg/mL against MRSA ATCC 43300, and had anti-glioma proliferation activity [111] while pyrrospirone J inhibited MRSA at a MIC value of 1.7 µg/mL [112].
The co-culture of a staghorn Gorgonian fungus, Rhinocladiella similis 35, from Luhuitou fringing reefs and actinomycete, S. rochei MB037 (South China Sea) resulted in isolation and identification of new fatty acids with rare nitrile group, a new chromone derivative,) and another two known 18-membered macrolides ( Table 2). Only compound 1 exhibited anti-MRSA activity against MRSA at MIC value of 0.195 µg/mL [113].

Marine-Derived Antimicrobial Compounds from Algae
A tropical marine Cyanobacterium, Okeania hirsuta (Republic of Panama), has synthesized a potent polyhydroxy macrolide, bastimolide A. This 40-membered ring macrolide has one 1, 3-diol, one 1, 3, 5-triol, six 1, 5-diols, and one tert-butyl group. The pure form of this compound showed moderate cytotoxic effect and potent antimalarial activity against MDR strains of P falciparum (IC 50 80-270 nM). These make it a potentially promising lead for antimalarial drug discovery and further research [114].
Baltic Sea brown alga, Fucus vesiculosus, was sampled throughout the year to check its potential relation to the bioactivity profile. About 44 compounds were putatively identified, including phlorotannins phlorotannins, phosphatidylcholine, betaine lipids and their lyso derivatives, chlorophylls, and carotenoids. The extract exhibited other biological activities and had no antimicrobial activity against some fungi and ESKAPE panel of human bacterial pathogens except MRSA (100 µg/mL) [118]. In addition to the antiproliferative and neuroprotective activities of kappa-carrageenan extracted from a marine alga, Hypnea musciformis (Brazil), it exhibited antimicrobial activity including against MDR C. albicans 10231 at IC 50 value of 147.3 µg/mL [2].
An unusual diterpene glycosides (with a sterically encumbered cyclopropane core), peyssonnosides A−B, were produced by Peyssonnelia sp. sampled at Solomon Islands, Georgia, USA. The compound showed no cytotoxic effect and exhibited antimicrobial activity against test pathogens, including MRSA at MIC 90 of 16.7 ± 0.3 and >50 µg/mL, respectively [119].
The methanol extract of microalgae, dinoflagellates, Amphidinium carterae led to the isolation of a bioactive polyketides, new amphidinol (amphidinol 22) and two other known amphidinols, with cytotoxic and antifungal properties. It moderately inhibited C. albicans ATCC 64124 less than amphidinol A (19 µg/mL) and had no activity against other drug-resistant pathogens, such as K. pneumoniae ATCC700603, and MRSA MB5393 [120].

Marine-Derived Antimicrobial Compounds from Invertebrates
Two marine sponges, Dysidea granulosa and Dysidea spp. (United States), produced potent anti-MRSA polybrominated diphenyl ethers, such as 2-(20, 40-dibromophenoxy)-3, 4, 5-tribromophenol (2) (the most potent), and the compounds exhibited potent and broad-spectrum activity against both Gram-negative and Gram-positive bacteria including, MRSA at MIC value of 0.1 mg/mL. This suggests that these compounds could be useful in drug development in the future [121].
The bioactivity-guided fractionation of sponges (Lamellodysidea sp. and Dysidea granulosa (2)) from Papua New Guinea led the researchers to identify fourteen polybrominated, diphenyl ethers, including a new methoxy-containing compound (8). These compounds displayed strong to moderate antimicrobial activity against test pathogens (Table 2) [123].
The reports on the antibacterial macromolecules from tunicates are relatively few, which led Wang et al. to isolate and identify butenolide metabolites from Pseudodistoma antinboja (South Sea, Korea). These class of cadiolide, cadiolides J-M, 1, 3-5, and cadiolide H (2) exhibited considerable antimicrobial activity comparable to the commercial drugs (such as vancomycin and linezolid) against pathogens including four strains of MRSA (1-8 µg/mL) [124].
Compounds with potent antioxidant and antibacterial activities were purified from an edible portion of Chinese Sea Arca inflat. The authors identified the compound to be a new sarcoplasmic calcium-binding protein-like metabolite, named protein (J2-C4), which had moderate inhibitory activity against MRSA (MIC = 750 µg/mL) [126]. This indicated that the protein could be harnessed and developed as a potential food additive.

Conclusions
About 119 articles were included in this review, and the marine natural products were obtained from 55 bacteria, 48 fungi, 8 algae, and 8 invertebrates. The structure and anti-drug resistant activities of some of the MNPs are summarized in Tables 2 and 3, and Figures 2-4. It is evident from these articles that marine natural products are diverse, abundant, and could evidently serve as a ray of light in the therapy of drug-resistant bacterial, fungal, and parasitic infections, and could also be translated to novel biomedicines. As more MNPs continue to enter clinical trials, more novel compounds with different chemical structures and biological activities are being discovered. However, one of the hurdles in natural product discovery is the high rate of repeated isolation of known compounds.
It is clear that the majority of isolated MNPs came from bacteria (specifically actinomycetes) and fungi. Most of the compounds were active against drug-resistant pathogens and have other biological properties not discussed here. Genetic engineering of isolated marine microbes through genomic analyses and applying metabolic approach and employing combined biomedical and biotechnological efforts, more novel compounds will be discovered, and the yield of bioactive metabolites will increase. Finally, to make the discovery of and accessibility to natural products easier, there is a need to develop automated and more affordable techniques for the isolation and identification of marine natural products.
Supplementary Materials: The following are available online at http://www.mdpi.com/1660-3397/18/3/145/s1, Figures S1 and S2: the structures of some of compounds reported in 2019 and Table S1: summary of some of the articles on marine natural products tested against drug-resistant pathogens.

Conflicts of Interest:
The authors declare no conflict of interest.