Anti-Infective Secondary Metabolites of the Marine Cyanobacterium Lyngbya Morphotype between 1979 and 2022

Cyanobacteria ascribed to the genus Lyngbya (Family Oscillatoriaceae) represent a potential therapeutic gold mine of chemically and biologically diverse natural products that exhibit a wide array of biological properties. Phylogenetic analyses have established the Lyngbya ‘morpho-type’ as a highly polyphyletic group and have resulted in taxonomic revision and description of an additional six new cyanobacterial genera in the same family to date. Among the most prolific marine cyanobacterial producers of biologically active compounds are the species Moorena producens (previously L. majuscula, then Moorea producens), M. bouillonii (previously L. bouillonii), and L. confervoides. Over the years, compounding evidence from in vitro and in vivo studies in support of the significant pharmaceutical potential of ‘Lyngbya’-derived natural products has made the Lyngbya morphotype a significant target for biomedical research and novel drug leads development. This comprehensive review covers compounds with reported anti-infective activities through 2022 from the Lyngbya morphotype, including new genera arising from recent phylogenetic re-classification. So far, 72 anti-infective secondary metabolites have been isolated from various Dapis, Lyngbya, Moorea, and Okeania species. These compounds showed significant antibacterial, antiparasitic, antifungal, antiviral and molluscicidal effects. Herein, a comprehensive literature review covering the natural source, chemical structure, and biological/pharmacological properties will be presented.


Introduction
Infectious diseases, also known as transmissible diseases or communicable diseases, are illnesses caused by a harmful pathogen. Infections can be a result of a wide range of pathogens, such as bacteria, viruses, parasites, and fungi. The immune system of the host is always responsible for the fight against the cause of infection. Anti-infective drugs have improved the way for modern medicine and saved the life of millions of people. They are considered a vital group of drugs in this regard and have contributed significantly to the improvement of lifestyle and the rise in life expectation over the past decades [1,2]. Natural products contributed significantly to the major group of current anti-infective drugs [3]. However, for a long time, the pharmaceutical industry has ignored the search for natural product-derived and novel anti-infective drug discovery [4]. This fact resulted in a situation where illness with antibiotic resistant microbes regularly cannot be effectively treated [5]. Illnesses with Gram-negative bacteria and a developed treatment resistance, such as Enterobacter and Pseudomonas, are considered serious issues, while a few new antibiotics are under development [6].
The development of Antimicrobial Resistance (AMR) and multi-drug resistance to current therapeutics represent a serious issue for the patients, health care system and Interestingly, more than 50% of the reported compounds come from L. majuscula (Table 1). These species have been collected from locations around the world, focused on tropical regions (Figure 1).
A notable number of reported compounds (17%) comes from species that collected in Panama, making this place a diverse and rich location for collecting cyanobacterial strains. Japan comes in the second place with 9 compounds (13%) followed by Guam with 8 compounds (11%). In third place, Florida (USA), Red Sea and Japan, each comes with 6 compounds (8%). (Figure 2).
These data indicate that genus Lyngbya continues to be a rich source of secondary metabolites that are new to science and suggest potential locations for further discovery. These data indicate that genus Lyngbya continues to be a rich source of secondary metabolites that are new to science and suggest potential locations for further discovery.

Compounds with Antibacterial Activities
Among the diverse bioactivities that Lyngbya secondary metabolites have displayed is the activity against bacteria. In 1979, malyngolide (1) (Figure 3), a δ-lactone was reported from Hawaiian Lyngbya majuscula in Kahala Beach, showed effective antibacterial activity against Mycobacterium smegmatis and Streptococcus pyogenes and was less active against These data indicate that genus Lyngbya continues to be a rich source of secondary metabolites that are new to science and suggest potential locations for further discovery.

Compounds with Antibacterial Activities
Among the diverse bioactivities that Lyngbya secondary metabolites have displayed is the activity against bacteria. In 1979, malyngolide (1) (Figure 3), a δ-lactone was reported from Hawaiian Lyngbya majuscula in Kahala Beach, showed effective antibacterial activity against Mycobacterium smegmatis and Streptococcus pyogenes and was less active against Staphylococcus aureus and Bacillus subtilis, and inactive towards Enterobacter aerogenes, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis, and Staphylococcus marcescens [40].

Compounds with Antibacterial Activities
Among the diverse bioactivities that Lyngbya secondary metabolites have displayed is the activity against bacteria. In 1979, malyngolide (1) (Figure 3), a δ-lactone was reported from Hawaiian Lyngbya majuscula in Kahala Beach, showed effective antibacterial activity against Mycobacterium smegmatis and Streptococcus pyogenes and was less active against Staphylococcus aureus and Bacillus subtilis, and inactive towards Enterobacter aerogenes, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis, and Staphylococcus marcescens [40].
Mar. Drugs 2022, 20, x FOR PEER REVIEW The related amide of lyngbic acid, malyngamide D acetate (3) (Figure 3), whi isolated from Caribbean L. majuscula in Isla Guayacan, Puerto Rico in 1987, di slight activity against S. aureus [42]. In 2001, the cyclic depsipeptides pitipeptolides A (4) and B (5) (Figure 4) are r from L. majuscula collected in Piti Bomb Holes, Guam [43]. The compounds di moderate activity against Mycobacterium tuberculosis strains (ATCC 25177 and 35818) in the antimycobacterial diffusion susceptibility assay. Pitipeptolide A (4 diameter of growth inhibition zone for ATCC 25177 strain equivalent to 25 and and for ATCC 35818 strain equivalent to 15 and 9 mm upon treatment with 100 an respectively. Pitipeptolide B (5) gave a diameter of growth inhibition zone for ATC strain equivalent to 30 and 15 mm, and for ATCC 35818 strain equivalent to 15 and upon treatment with 100 and 25 µg, respectively. For comparison, treatments w and 1 µg of streptomycin resulted in superior activity, giving diameters of 50, 1 mm, respectively, for ATCC 25177 strain, and 55, 33 and 10 mm, respectively, fo 35818 [43].
In 2001, the cyclic depsipeptides pitipeptolides A (4) and B (5) (Figure 4) are reported from L. majuscula collected in Piti Bomb Holes, Guam [43]. The compounds displayed moderate activity against Mycobacterium tuberculosis strains (ATCC 25177 and ATCC 35818) in the antimycobacterial diffusion susceptibility assay. Pitipeptolide A (4) gave a diameter of growth inhibition zone for ATCC 25177 strain equivalent to 25 and 10 mm, and for ATCC 35818 strain equivalent to 15 and 9 mm upon treatment with 100 and 25 µg, respectively. Pitipeptolide B (5) gave a diameter of growth inhibition zone for ATCC 25177 strain equivalent to 30 and 15 mm, and for ATCC 35818 strain equivalent to 15 and 10 mm upon treatment with 100 and 25 µg, respectively. For comparison, treatments with 25, 5 and 1 µg of streptomycin resulted in superior activity, giving diameters of 50, 15 and 0 mm, respectively, for ATCC 25177 strain, and 55, 33 and 10 mm, respectively, for ATCC 35818 [43].
The related amide of lyngbic acid, malyngamide D acetate (3) (Figure 3), which wer isolated from Caribbean L. majuscula in Isla Guayacan, Puerto Rico in 1987, displayed slight activity against S. aureus [42]. In 2001, the cyclic depsipeptides pitipeptolides A (4) and B (5) (Figure 4) are reported from L. majuscula collected in Piti Bomb Holes, Guam [43]. The compounds displayed moderate activity against Mycobacterium tuberculosis strains (ATCC 25177 and ATCC 35818) in the antimycobacterial diffusion susceptibility assay. Pitipeptolide A (4) gave a diameter of growth inhibition zone for ATCC 25177 strain equivalent to 25 and 10 mm and for ATCC 35818 strain equivalent to 15 and 9 mm upon treatment with 100 and 25 µg respectively. Pitipeptolide B (5) gave a diameter of growth inhibition zone for ATCC 2517 strain equivalent to 30 and 15 mm, and for ATCC 35818 strain equivalent to 15 and 10 mm upon treatment with 100 and 25 µg, respectively. For comparison, treatments with 25, 5 and 1 µg of streptomycin resulted in superior activity, giving diameters of 50, 15 and mm, respectively, for ATCC 25177 strain, and 55, 33 and 10 mm, respectively, for ATCC 35818 [43].
SAR studies revealed that the N-methylation in the Phe unit is essential for both cytotoxic and antibacterial activities, whereas the π system in the fatty acid unit was found to be one of the important structural features for the cytotoxic activity in mammalian cells, but it was not required for antibacterial activity. Furthermore, decreasing the hydrophobicity of certain units (2-Hydroxy 3-methyl pentanoic acid (Hmpa) → 2-Hydroxy isovaleric acid (Hiva) and Ile → Val) caused a reduction in the anticancer activity (as seen with pitipeptolides E and F), while on the other hand resulted in an increase in antimycobacterial potency (particularly pitipeptolide F) [44].
Pitiprolamide (10) ( Figure 5), a dolastatin 16 analog and a proline rich cyclic depsipeptide was purified in 20111 from the same Guamanian cyanobacterium Lyngbya majuscula collected at Piti Bomb Holes, displayed weak antimycobacterial effect against M. tuberculosis (ATCC 25177 strain) starting at 50 µg in a disk diffusion assay. The compound displayed zone of inhibition of 23, 13 and 0 mm after 100, 50 and 10 µg treatment. Also, the compound exerted weak antibacterial activity against Bacillus cereus (ATCC 10987 strain) starting at 1 µM in a microtiter plate-based assay with an approximate IC 50 value of 70 µM and lacked the activity against S. aureus and P. aeruginosa [45].
ar. Drugs 2022, 20, x FOR PEER REVIEW SAR studies revealed that the N-methylation in the Phe unit is essenti totoxic and antibacterial activities, whereas the π system in the fatty acid u to be one of the important structural features for the cytotoxic activity in ma but it was not required for antibacterial activity. Furthermore, decreasing t bicity of certain units (2-Hydroxy 3-methyl pentanoic acid (Hmpa) → 2-H leric acid (Hiva) and Ile → Val) caused a reduction in the anticancer activity pitipeptolides E and F), while on the other hand resulted in an increase in a rial potency (particularly pitipeptolide F) [44].
Pitiprolamide (10) ( Figure 5), a dolastatin 16 analog and a proline ri sipeptide was purified in 20111 from the same Guamanian cyanobacterium juscula collected at Piti Bomb Holes, displayed weak antimycobacterial eff tuberculosis (ATCC 25177 strain) starting at 50 µg in a disk diffusion assay. T displayed zone of inhibition of 23, 13 and 0 mm after 100, 50 and 10 µg tre the compound exerted weak antibacterial activity against Bacillus cereus strain) starting at 1 µM in a microtiter plate-based assay with an approxim of 70 µM and lacked the activity against S. aureus and P. aeruginosa [45].  Table 2 that purified in 2013 from the cyanobacterium M. producens c Red Sea, near Jeddah, Saudi Arabia, significantly inhibited the growth of H37Rv in vitro (65% inhibition) at a concentration of 12.5 µg/mL, while th lipopetides malyngamides A (11), B (12) and 4 (13) ( Figure 6) (obtained f cyanobacterial collection) displayed much weaker antimycobacterial activi tested concentration, which was deemed as ineffective (18, 10 and 17% inhi tively) [41]. This result suggests the importance of a terminal free carboxyl for the antimycobacterial effect.
Another group of antimicrobial natural products is the cyclic un lyngbyazothrins A and B (14 and 15) and C and D (16 and 17) (   Table 2 that purified in 2013 from the cyanobacterium M. producens collected at the Red Sea, near Jeddah, Saudi Arabia, significantly inhibited the growth of M. tuberculosis H 37 Rv in vitro (65% inhibition) at a concentration of 12.5 µg/mL, while the chlorinated lipopetides malyngamides A (11), B (12) and 4 (13) ( Figure 6) (obtained from the same cyanobacterial collection) displayed much weaker antimycobacterial activity at the same tested concentration, which was deemed as ineffective (18, 10 and 17% inhibition, respectively) [41]. This result suggests the importance of a terminal free carboxylic acid moiety for the antimycobacterial effect.    and D (17) showed modest activity against B. subtilis SBUG 14 (25 µg/disk: 18 mm), E. coli ATCC 11229 (100 µg/disk: 18 mm), and E. coli SBUG 13 (100 µg/disk: 15 mm) and low activity against P. aeruginosa ATCC 27853 (100 µg/disk: 8 mm) and Serratia marcescens SBUG 9 (200 µg/disk: 8 mm). When used at the same concentrations, the lyngbyazothrins A and B (14 and 15) mixture lacked activity against the aforementioned strains, which suggests that the linkage of the acyl residue at C-5 of the 3-amino-2,5,7,8-tetrahydroxy-10methylundecanoic acid (Aound) unit may be responsible for the antimicrobial activity [46].       Table 2 summarizes all compounds with reported antibacterial effects, their sources and collection sites as well as the targeted bacteria and observed effects.

Compounds with Anti-Swarming and Anti-Quorum Sensing Activities
Some compounds exert their antibacterial activities by inhibiting swarming, a mechanism used by bacteria to spread across surfaces supplied with nutrients through the use of rotating flagella in order to speed their growth [48,49].

Compounds with Anti-Swarming and Anti-Quorum Sensing Activities
Some compounds exert their antibacterial activities by inhibiting swarming, anism used by bacteria to spread across surfaces supplied with nutrients through of rotating flagella in order to speed their growth [48,49].
Lagunamides A-C (21-23) (Figure 9), cyclic depsipeptides purified in 2010 a from L. majuscula found in Pulau Hantu Besar, Singapore, exhibited moderate anti-swarming activities against the Gram-negative bacterial strain P. aeruginosa P 56 and 49% compared to control, respectively) when tested at 100 ppm; P. aerugino (62,56 and 49% compared to control, respectively) when tested at 100 ppm [50,51 On the other hand, other compounds exert their antimicrobial activities by ing with quorum sensing (QS), a mechanism that is responsible for the regulatin bacterial gene expression in response to fluctuations in cell-population density [5 On the other hand, other compounds exert their antimicrobial activities by interfering with quorum sensing (QS), a mechanism that is responsible for the regulating of the bacterial gene expression in response to fluctuations in cell-population density [52,53].
In 2010, malyngamide C (24) and 8-epi-malyngamide C (25) ( Figure 10) are reported from L. majuscula collected in Bush Key, Dry Tortugas, Florida, displayed activity against the QS reported pSB1075, which expresses LasR and responds to 3-oxo-C 12 -HSL (N-3oxo-dodecanoyl-L-homoserine lactone). Using concentrations of both compounds that did not actually inhibit bacterial cell growth (10, 100 and 1000 µM) resulted in reducing 3-oxo-C 12 -HSL signalling in the QS reporter [54]. In 2010, malyngamide C (24) and 8-epi-malyngamide C (25) ( Figure 10) are r from L. majuscula collected in Bush Key, Dry Tortugas, Florida, displayed activity the QS reported pSB1075, which expresses LasR and responds to 3-oxo-C12-HSL (N dodecanoyl-L-homoserine lactone). Using concentrations of both compounds that actually inhibit bacterial cell growth (10, 100 and 1000 µM) resulted in reducing 3-HSL signalling in the QS reporter [54]. Malyngolide (1), an antibiotic isolated from L. majuscula in South Florida, inhibited violacein pigment production by Chromobacterium violaceum CV017 in the QS bioassay. Effective concentrations ranged from 0.07 to 0.22 mM, with an EC 50 value of 0.11 mM, and the growth of the C. violaceum reporter strain was not inhibited even at the higher concentration used (0.22 mM). In the presence of 14 µM of 3-oxo-C 12 -HSL, malyngolide (1) inhibited responses of the lasR + P lasI -luxCDABE reporter pSB1075 when used at concentrations ranging from 3.57 to 57 µM (EC 50 = 12.2 µM) without affecting bacterial growth. At these concentrations, malyngolide (1) also significantly reduced the production of elastase by P. aeruginosa PAO1, which is an extracellular enzyme regulated by 3-oxo-C 12 -HSL and LasR, with an EC 50 value of 10.6 µM. At higher concentrations of malyngolide, elastase production was inhibited to the level observed in the QS mutant of P. aeruginosa JP2. It is worth mentioning that a decline in the activity of malyngolide was noticed upon storing it in plastic instead of glass vials [55].

Mar. Drugs 2022, 20, x FOR PEER REVIEW
Another disruptor of QS in P. aeruginosa is lyngbyoic acid (26) (Figure 11), a small cyclopropane-containing fatty acid isolated was reported in 2019 from L. majuscula collected at various sites in Florida. The compound was evaluated against four reporters based on different acylhomoserine lactone (AHL) receptors (LuxR, AhyR, TraR and LasR), and LasR turned out to be the most reported being affected by lyngbyoic acid (26). It also reduced the production of pyocyanin and elastase (LasB) both on the protein and transcript level in wild-type P. aeruginosa, and directly inhibited LasB enzymatic activity with a K i of 5.4 mM, without affecting bacterial growth [56]. Malyngolide (1), an antibiotic isolated from L. majuscula in South Florida, inhibited violacein pigment production by Chromobacterium violaceum CV017 in the QS bioassay Effective concentrations ranged from 0.07 to 0.22 mM, with an EC50 value of 0.11 mM, and the growth of the C. violaceum reporter strain was not inhibited even at the higher concen tration used (0.22 mM). In the presence of 14 µM of 3-oxo-C12-HSL, malyngolide (1) inhib ited responses of the lasR + PlasI-luxCDABE reporter pSB1075 when used at concentrations ranging from 3.57 to 57 µM (EC50 = 12.2 µM) without affecting bacterial growth. At these concentrations, malyngolide (1) also significantly reduced the production of elastase by P aeruginosa PAO1, which is an extracellular enzyme regulated by 3-oxo-C12-HSL and LasR with an EC50 value of 10.6 µM. At higher concentrations of malyngolide, elastase produc tion was inhibited to the level observed in the QS mutant of P. aeruginosa JP2. It is worth mentioning that a decline in the activity of malyngolide was noticed upon storing it in plastic instead of glass vials [55].
Another disruptor of QS in P. aeruginosa is lyngbyoic acid (26) (Figure 11), a smal cyclopropane-containing fatty acid isolated was reported in 2019 from L. majuscula col lected at various sites in Florida. The compound was evaluated against four reporters based on different acylhomoserine lactone (AHL) receptors (LuxR, AhyR, TraR and LasR) and LasR turned out to be the most reported being affected by lyngbyoic acid (26). It also reduced the production of pyocyanin and elastase (LasB) both on the protein and tran script level in wild-type P. aeruginosa, and directly inhibited LasB enzymatic activity with a Ki of 5.4 mM, without affecting bacterial growth [56].  Finally, in 2019, doscadenamide A (27) (Figure 11), was isolated from M. bouillonii collected in Fingers Reef, Apra Harbor, Guam, displayed QS agonistic activities in a LasRdependent manner. Doscadenamide A and the QS signaling molecule 3-oxo-C 12 -HSL share structural similarities as they both contain a five-membered ring core and long alkyl side chain. Doscadenamide A activated the 3-oxo-C 12 -HSL-responsive reporter plasmid pSB1075, which encodes LasR and contains a light-producing luxCDABE cassette expressed in E. coli; however, it was not able to activate the related reporter pTIM5319, which is identical to pSB1075, except for lacking the AHL-binding site LasR, thereby suggesting that doscadenamide A activates QS via the AHL-binding site. The effect of the compound was tested on wild-type P. aeruginosa, using effective doses of 10, 100 and 1000 µM, and maximal induction of the QS pigment pyocyanin production was observed upon usage of even the lowest concentration. Levels of pyocyanin increased after only 6 h of treatment with 10 µM of doscadenamide A, which was a comparable result with using 10 µM of the positive control 3-oxo-C 12 -HSL [57]. Table 3 summarizes all compounds with reported anti-swarming and anti-quorum sensing effects, their sources and collection sites as well as the targeted bacteria and observed effects. L. bouillonii Guam 3-Oxo-C 12 -HSLresponsive reporter plasmid pSB1075, which encodes LasR and contains a light-producing luxCDABE cassette expressed in E. coli QS agonist in a LasR-dependent manner and activation of 3-oxo-C 12 -HSL-responsive reporter plasmid pSB1075 [57] Production of QS pigment pyocyanin in wild-type P. aeruginosa

Compounds with Antifungal Activities
Antifungal assays are among the widely used bioassays for testing the activities of natural compounds isolated from cyanobacteria. Majusculamide C (28) (Figure 12), a cyclic depsipeptide reported in 1984 from L. majuscula in Marshall Islands, inhibited the growth of a number of fungal plant pathogens such as Phytophthora infestans and Plasmopora viticola, the causative organisms of tomato late blight and grape downy mildew, respectively [58].

Compounds with Antifungal Activities
Antifungal assays are among the widely used bioassays for testing the acti natural compounds isolated from cyanobacteria. Majusculamide C (28) (Figure 1 clic depsipeptide reported in 1984 from L. majuscula in Marshall Islands, inhib growth of a number of fungal plant pathogens such as Phytophthora infestans and pora viticola, the causative organisms of tomato late blight and grape downy mild spectively [58]. In 1988, 57-normajusculamide C (29) (Figure 12) was purified from the mar nobacterium L. majuscula collected in Marshall Islands. The compound displayed cotic activity against the indicator organism Saccharomyces pastorianus [59]. The majority of natural products have been tested for their antifungal activity Candida albicans as reported herein. Laxaphycin B (32) (Figure 14), a cyclic lipope ported in 1997 from L. majuscula in Moorea Atoll, French Polynesia, exhibited an activity against C. albicans. Interestingly, laxaphycin A (33) (Figure 14), inactive b exerted a synergistic effect when combined with laxaphycin B (32) and potentia antifungal activity. This unique difference in activity might be attributed to the c In 1988, 57-normajusculamide C (29) (Figure 12) was purified from the marine cyanobacterium L. majuscula collected in Marshall Islands. The compound displayed antimycotic activity against the indicator organism Saccharomyces pastorianus [59].
Microcolins A (30) and B (31) (Figure 13), lipopeptides isolated from Floridian L. polychroa, showed only little activity against two strains (SIO and EBGJ) of the marine fungus Dendryphiella salina, which has been linked to diseases among marine algae and seagrasses, where the LD 50 values were above 200 µg/mL in the antifungal assay. The antifungal activities of microcolins A (30) and B (31), were significantly lower than the known antifungal compound amphotericin B, which resulted in 100% inhibition of marine fungus Dendryphiella salina in the same assay at concentrations as low as 3.13 µg/mL [60].

Compounds with Antifungal Activities
Antifungal assays are among the widely used bioassays for testing the activ natural compounds isolated from cyanobacteria. Majusculamide C (28) (Figure 1 clic depsipeptide reported in 1984 from L. majuscula in Marshall Islands, inhib growth of a number of fungal plant pathogens such as Phytophthora infestans and pora viticola, the causative organisms of tomato late blight and grape downy mild spectively [58]. In 1988, 57-normajusculamide C (29) (Figure 12) was purified from the mar nobacterium L. majuscula collected in Marshall Islands. The compound displayed cotic activity against the indicator organism Saccharomyces pastorianus [59]. Microcolins A (30) and B (31) (Figure 13), lipopeptides isolated from Floridia ychroa, showed only little activity against two strains (SIO and EBGJ) of the marine Dendryphiella salina, which has been linked to diseases among marine alg seagrasses, where the LD50 values were above 200 µg/mL in the antifungal assay. tifungal activities of microcolins A (30) and B (31), were significantly lower t known antifungal compound amphotericin B, which resulted in 100% inhibition of fungus Dendryphiella salina in the same assay at concentrations as low as 3.13 µg/m The majority of natural products have been tested for their antifungal activity Candida albicans as reported herein. Laxaphycin B (32) (Figure 14), a cyclic lipope ported in 1997 from L. majuscula in Moorea Atoll, French Polynesia, exhibited an activity against C. albicans. Interestingly, laxaphycin A (33) (Figure 14), inactive b exerted a synergistic effect when combined with laxaphycin B (32) and potentia antifungal activity. This unique difference in activity might be attributed to the c The majority of natural products have been tested for their antifungal activity against Candida albicans as reported herein. Laxaphycin B (32) (Figure 14), a cyclic lipopetide reported in 1997 from L. majuscula in Moorea Atoll, French Polynesia, exhibited antifungal activity against C. albicans. Interestingly, laxaphycin A (33) (Figure 14), inactive by itself, exerted a synergistic effect when combined with laxaphycin B (32) and potentialized its antifungal activity. This unique difference in activity might be attributed to the chemical structures of the compounds. Laxaphycin A (33) is an undecapeptide with segregated hydrophobic and hydrophilic residues, while laxaphycin B (32) is a dodecapeptide with alternating hydrophobic and hydrophilic residues [61].
structures of the compounds. Laxaphycin A (33) is an undecapeptide with segregated hydrophobic and hydrophilic residues, while laxaphycin B (32) is a dodecapeptide with alternating hydrophobic and hydrophilic residues [61]. Tanikolide (34) (Figure 15), a lipid lactone that was reported in 1999 from L. majuscula found in Tanikeli Island, Madagascar, showed antifungal activity towards C. albicans with 13 mm diameter zone of inhibition at 100 µg/disk using paper disk-agar plate methodology [62].
Lyngbyabellin B (35) (Figure 15), a cyclic depsipeptide that reported in 2000 from L. majuscula found in Dry Tortugas National Park in Florida, displayed antifungal effect towards C. albicans (ATCC 14053) in a disk diffusion assay with a 10.5 mm zone of inhibition at 100 µg/disk and a slight halo at 10 µg/disk [63].
In 2002, the lipopeptide hectochlorin (36) (Figure 15), was reported from L. majuscula found in both Hector Bay, Jamaica, and Boca del Drago Beach, Panama. The compound produced a 16 mm zone of inhibition at 100 µg/disk and an 11 mm zone of inhibition at 10 µg/disk against C. albicans (ATCC 14053) [64].  Tanikolide (34) (Figure 15), a lipid lactone that was reported in 1999 from L. majuscula found in Tanikeli Island, Madagascar, showed antifungal activity towards C. albicans with 13 mm diameter zone of inhibition at 100 µg/disk using paper disk-agar plate methodology [62]. Tanikolide (34) (Figure 15), a lipid lactone that was reported in 1999 from L. m found in Tanikeli Island, Madagascar, showed antifungal activity towards C. albic 13 mm diameter zone of inhibition at 100 µg/disk using paper disk-agar plate me ogy [62].
Lyngbyabellin B (35) (Figure 15), a cyclic depsipeptide that reported in 2000 majuscula found in Dry Tortugas National Park in Florida, displayed antifungal e wards C. albicans (ATCC 14053) in a disk diffusion assay with a 10.5 mm zone of in at 100 µg/disk and a slight halo at 10 µg/disk [63].
In 2002, the lipopeptide hectochlorin (36) (Figure 15), was reported from L. m found in both Hector Bay, Jamaica, and Boca del Drago Beach, Panama. The com produced a 16 mm zone of inhibition at 100 µg/disk and an 11 mm zone of inhib 10 µg/disk against C. albicans (ATCC 14053) [64].  Lyngbyabellin B (35) (Figure 15), a cyclic depsipeptide that reported in 2000 from L. majuscula found in Dry Tortugas National Park in Florida, displayed antifungal effect towards C. albicans (ATCC 14053) in a disk diffusion assay with a 10.5 mm zone of inhibition at 100 µg/disk and a slight halo at 10 µg/disk [63].
In 2002, the lipopeptide hectochlorin (36) (Figure 15), was reported from L. majuscula found in both Hector Bay, Jamaica, and Boca del Drago Beach, Panama. The compound produced a 16 mm zone of inhibition at 100 µg/disk and an 11 mm zone of inhibition at 10 µg/disk against C. albicans (ATCC 14053) [64].
A mixture of lobocyclamides A (37) and B (38) exhibited significant synergism (e.g., 1:1 mixture of A and B produced a MIC of 10-30 µg/mL) with higher activity than either of the pure compounds used individually [65], a phenomenon also reported with laxaphycins A (33) and B (32) [61].  Table 4 summarizes all compounds with reported antifungal activities, their sources and collection sites as well as the targeted fungi and observed effects.  In the microbroth dilution assay against C. albicans 96-489, lobocyclamide A (37) displayed MIC value of 100 µg/mL, while lobocyclamide B (38) showed an MIC value of 30-100 µg/mL [65].
A mixture of lobocyclamides A (37) and B (38) exhibited significant synergism (e.g., 1:1 mixture of A and B produced a MIC of 10-30 µg/mL) with higher activity than either of the pure compounds used individually [65], a phenomenon also reported with laxaphycins A (33) and B (32) [61]. Table 4 summarizes all compounds with reported antifungal activities, their sources and collection sites as well as the targeted fungi and observed effects.

Compounds with Antiparasitic Activities
Tropical parasitic diseases can be life-threatening if not treated appropriately from an early stage. The most common tropical infectious parasite is Plasmodium falciparum, the causative organism of malaria. Several Lyngbya-derived compounds displayed inhibitory activities on this parasite.
On the other hand, the nonaromatic analog, dragonamide B (43) (Figure 18), was reported from a L. majuscula collected in Panama in 2007, was found to be completely inactive suggesting the necessity of an aromatic amino acid moiety at the carboxy terminus for the antimalarial activity [66]. Interestingly, when dragonamide A (42) was subjected to the same antimalarial assay on a later date, no activity was shown against the parasite (maximum test concentration 10 µM) [67].
Ikoamide (45) (Figure 19), an antimalarial lipopeptide reported in 2020 from a marine cyanobacterium Okeania sp. collected in Okinawa, Japan. The compound displayed strong antimalarial activity against P. falciparum with an IC50 value of 0.14 µM without cytotoxicity against human cancer cell lines (HeLa and HL60) at 10 µM [69].   cyanobacterium Okeania sp. collected in Okinawa, Japan. The compound displayed stron antimalarial activity against P. falciparum with an IC50 value of 0.14 µM without cytotox city against human cancer cell lines (HeLa and HL60) at 10 µM [69].   Bastimolide B (47) (Figure 21), a 24-membered polyhydroxy macrolide with a long aliphatic polyhydroxylated side chain and unique terminal tertbutyl group was purified from Okeania hirsuta collected in Panama [71]. It showed a strong antimalarial activity against chloroquine-sensitive P. falciparum strain HB3 with IC50 of 5.7 µM.
Another tropical parasite, which is the causative organism of the disease leishmaniasis, is Leishmania donovani. Antileishmanial activity has been displayed by a number of compounds isolated from Lyngbya sp.
Dragonamides A (42) ( Figure 17) and E (53) (Figure 23) and herbamide B (54) (Figure 23), modified linear lipopeptides isolated in 2010 from Panamanian L. majuscula found around mangrove roots in the Bastimentos National Park, Bocas del Toro, Panama, showed inhibitory activities against L. donovani (LD-1S/MHOM/SD/00-strain 1S) with IC 50 values of 6.5, 5.1 and 5.9 µM, respectively [67].  Almiramides B (55) and C (56) (Figure 24), members of another class of linear lipopeptides isolated in 2010 from the Panamanian collection of the marine cyanobacterium Lyngbya majuscula, also exhibited antileishmanial activities, with IC50 values of 2.4 and 1.9 µM, respectively, whereas almiramide A (57) (Figure 24) was completely inactive up to 13.5 µM. This lack of activity might be attributed to the absence of an unsaturated terminus on the side chain, which was present in the active compounds, almiramides B (55) and C (56). Additionally, these compounds did not exert significant cytotoxicity to mammalian Vero cells and were selective for parasitic cells [74]. Almiramides B (55) and C (56) (Figure 24), members of another class of linear lipopeptides isolated in 2010 from the Panamanian collection of the marine cyanobacterium Lyngbya majuscula, also exhibited antileishmanial activities, with IC 50 values of 2.4 and 1.9 µM, respectively, whereas almiramide A (57) (Figure 24) was completely inactive up to 13.5 µM. This lack of activity might be attributed to the absence of an unsaturated terminus on the side chain, which was present in the active compounds, almiramides B (55) and C (56). Additionally, these compounds did not exert significant cytotoxicity to mammalian Vero cells and were selective for parasitic cells [74]. and 1.9 µM, respectively, whereas almiramide A (57) (Figure 24) was completely up to 13.5 µM. This lack of activity might be attributed to the absence of an unsa terminus on the side chain, which was present in the active compounds, almiram (55) and C (56). Additionally, these compounds did not exert significant cytotox mammalian Vero cells and were selective for parasitic cells [74]. It was found that dudawalamides A (58) and D (61) were more potent again ciparum with IC50 values of 3.6 and 3.5 µM, respectively, compared to dudawalam (59) and C (60) (IC50 = 8.0 and 10 µM, respectively). Dudawalamides A (58) and possessed 12 and 7% growth inhibition at 10 µg/mL, respectively, against T. cru they both had an IC50 value >10 µM against L. donovani. Dudawalamide D (61) most potent antiparasitic compound in this series since it exhibited an IC50 value of against L. donovani, and inhibited T. cruzi by 60% when used at a concentratio µg/mL [75].
It is interesting to note that cyclic depsipeptides with 2,2-dimethy-3-hydrox tynoic acid (Dhoya) moiety, which belong to the kulolide superfamily, possess onl differences in structure and stereochemistry between each other; nevertheless, th tency was affected by such slight changes, indicating the significant role that config and residue sequence plays in the bioactivity of this class of compounds [75].  In 2020, the linear peptides iheyamides A-C (62-64) ( Figure 26) were reported from the cyanobacterium Dapis sp., collected in Okinawa, Japan [76]. Iheyamide A (62) showed moderate antitrypanosomal effect against Trypanosoma brucei rhodesiense and T. bhurstuerusei brucei with an IC50 value of 1.5 µM. It was found that the isopropyl-O-Mepyrrolinone moiety is essential for the antitrypanosomal activity [76]. It was found that dudawalamides A (58) and D (61) were more potent against P. falciparum with IC 50 values of 3.6 and 3.5 µM, respectively, compared to dudawalamides B (59) and C (60) (IC 50 = 8.0 and 10 µM, respectively). Dudawalamides A (58) and B (59) possessed 12 and 7% growth inhibition at 10 µg/mL, respectively, against T. cruzi, and they both had an IC 50 value > 10 µM against L. donovani. Dudawalamide D (61) was the most potent antiparasitic compound in this series since it exhibited an IC 50 value of 2.6 µM against L. donovani, and inhibited T. cruzi by 60% when used at a concentration of 10 µg/mL [75].
It is interesting to note that cyclic depsipeptides with 2,2-dimethy-3-hydroxy-7-octynoic acid (Dhoya) moiety, which belong to the kulolide superfamily, possess only minor differences in structure and stereochemistry between each other; nevertheless, their potency was affected by such slight changes, indicating the significant role that configuration and residue sequence plays in the bioactivity of this class of compounds [75].
Finally, the polyketide beru'amide (66) (Figure 27) with 4S,5R-configuration was purified in very small amount (68 µg) from a cyanobacterium Okeania sp. collected in Kagoshima, Japan. Two synthetic enantiomers of beru'amide, 4S,5R and 4R,5S, were prepared and evaluated for their growth inhibition effects the causative parasite of African sleeping sickness Trypanosoma brucei rhodesiensec strains IL-1501. Interestingly, the enantiomers 4S,5R and 4R,5S of beru'amide displayed a closely similar and strong antitrypanosomal activity against Trypanosoma brucei rhodesiense with IC50 values of 1.2 and 1.0 µM, respectively. Accordingly, the absence of any noteworthy variance in the antitrypanosomal activities between the synthetic enantiomers, 4S,5R and 4R,5S, suggests that the absolute configurations are insignificant for the antitrypanosomal effect [78].  Table 5 displays all compounds with reported antiparasitic activities and collection sites as well as the targeted parasites and observed effects.  Finally, the polyketide beru'amide (66) (Figure 27) with 4S,5R-configuration was purified in very small amount (68 µg) from a cyanobacterium Okeania sp. collected in Kagoshima, Japan. Two synthetic enantiomers of beru'amide, 4S,5R and 4R,5S, were prepared and evaluated for their growth inhibition effects the causative parasite of African sleeping sickness Trypanosoma brucei rhodesiensec strains IL-1501. Interestingly, the enantiomers 4S,5R and 4R,5S of beru'amide displayed a closely similar and strong antitrypanosomal activity against Trypanosoma brucei rhodesiense with IC 50 values of 1.2 and 1.0 µM, respectively. Accordingly, the absence of any noteworthy variance in the antitrypanosomal activities between the synthetic enantiomers, 4S,5R and 4R,5S, suggests that the absolute configurations are insignificant for the antitrypanosomal effect [78]. Table 5 displays all compounds with reported antiparasitic activities, their sources and collection sites as well as the targeted parasites and observed effects.

Compounds with Antiviral Activities
Purification of the culture of the marine cyanobacterium L. lagerheimii that was collected in Hawaii resulted in the purification of two sulfoglycolipids (compounds 67 and 68) ( Figure 28). The compounds displayed activity against HIV-1 in cultured lymphoblastoid CEM, LDV-7, MT-2 and C3-44 cell lines in the tetrazolium assay and inp24 viral protein and syncytium formation assay [79]. The degree of inhibition HIV-1 by the compounds was generally comparable within a given cell line, but the degree of protection varied substantially among the different cell lines. The protective effects of the compounds were studied over a wide range of concentration range (about l-l00 µg/mL), depending on the target cell line and the mode of infection. Both compounds displayed similar levels of activity, suggesting that the length of the aliphatic side chain length and degree of unsaturation have no critical effect on the potency. Interestingly, sulfoglycolipids represent the first cyanobacterial derived compounds with antiviral activity [79].
tein and syncytium formation assay [79]. The degree of inhibition HIV-1 by th pounds was generally comparable within a given cell line, but the degree of pr varied substantially among the different cell lines. The protective effects of th pounds were studied over a wide range of concentration range (about l-l00 µg/m pending on the target cell line and the mode of infection. Both compounds display ilar levels of activity, suggesting that the length of the aliphatic side chain length gree of unsaturation have no critical effect on the potency. Interestingly, sulfogly represent the first cyanobacterial derived compounds with antiviral activity [79]. In another studies, sulfoglycolipids inhibited the DNA polymerase functio HIV-1 RT with IC50 values in the range 24-2950 nM without any significant effec ribonuclease H [80,81]. It was described that, the existence of a sulfate moiety in th part as well as the aliphatic side chain are crucial for sulfoglycolipid's effect on [81]. Table 6 displays the compounds with reported antiviral activities, their sour collection sites as well as the targeted viruses and observed effects.  In another studies, sulfoglycolipids inhibited the DNA polymerase function of the HIV-1 RT with IC 50 values in the range 24-2950 nM without any significant effect on the ribonuclease H [80,81]. It was described that, the existence of a sulfate moiety in the sugar part as well as the aliphatic side chain are crucial for sulfoglycolipid's effect on HIV RT [81]. Table 6 displays the compounds with reported antiviral activities, their sources and collection sites as well as the targeted viruses and observed effects.  (Table 7) Snails and slugs can damage crops by feeding on them; therefore, farmers and gardeners depend on molluscicides to protect their plants. There are some chemical compounds isolated from Lyngbya that possess molluscicidal activities.
In addition, in 1996, a chlorinated lipopeptide, barbamide (69) (Figure 29), was reported from L. majuscula collected from Barbara Beach in Curaçao. It showed toxic effect on the mollusc Biomphalaria glabrata with LC 100 of 10 µg/mL [82]. (Table 7) Snails and slugs can damage crops by feeding on them; therefore, fa deners depend on molluscicides to protect their plants. There are some pounds isolated from Lyngbya that possess molluscicidal activities.
In addition, in 1996, a chlorinated lipopeptide, barbamide (69) (Figu ported from L. majuscula collected from Barbara Beach in Curaçao. It show on the mollusc Biomphalaria glabrata with LC100 of 10 µg/mL [82].      Table 7 displays the compounds with reported molluscicidal and anti-diatom ties, their sources and collection sites as well as the targeted organism and observed In 2021, debromooscillatoxin G (71) and I (72) ( Figure 31) were purified from an Okinawan cyanobacterium Moorea prducens. Both compounds moderately inhibited the growth of the marine diatom Nitzschia amabilis at a concentration of 10 µg/mL by 30% and 50%, respectively [84]. Finally, in 2010, the greatest potency of molluscicidal activity against B. glabrata was observed with cyanolide A (70) (Figure 30), a glycosidic macrolide isolated from Papua New Guinean L. bouillonii in Pigeon Island. The compound displayed molluscicidal effect with LC50 value against B. glabrata of 1.2 µM [83]. In 2021, debromooscillatoxin G (71) and I (72) (Figure 31) were purified from an Okinawan cyanobacterium Moorea prducens. Both compounds moderately inhibited the growth of the marine diatom Nitzschia amabilis at a concentration of 10 µg/mL by 30% and 50%, respectively [84].  Table 7 displays the compounds with reported molluscicidal and anti-diatom activities, their sources and collection sites as well as the targeted organism and observed effects  Table 7 displays the compounds with reported molluscicidal and anti-diatom activities, their sources and collection sites as well as the targeted organism and observed effects

Summary
Secondary metabolites originating from the marine Lyngbya morphotype showed a huge chemical diversity and important biological activities, providing an unexploited potential for biodiscovery and therapeutics' candidates. This marine-inspired genus Lyngbya has been a vital example since its first discovery back in 1979 as an untapped resource of marine-derived drug candidates. The existence of 72 compounds with anti-infective properties of marine derived Lyngbya morphotype worldwide (Figure 1), together with more than 40 years (Figure 32) of research efforts fashioned a resource empowering the biosynthetic capabilities of this genus. In aquatic environments, members of the marine derived Lyngbya morphotype have typically been obtained from different locations worldwide. Accordingly, the interest in marine derived Lyngbya species was growing, and became an essential source of chemical diversity with anti-infective effects.
huge chemical diversity and important biological activities, providing an unexploited potential for biodiscovery and therapeutics' candidates. This marine-inspired genus Lyngbya has been a vital example since its first discovery back in 1979 as an untapped resource of marine-derived drug candidates. The existence of 72 compounds with anti-infective properties of marine derived Lyngbya morphotype worldwide (Figure 1), together with more than 40 years (Figure 32) of research efforts fashioned a resource empowering the biosynthetic capabilities of this genus. In aquatic environments, members of the marine derived Lyngbya morphotype have typically been obtained from different locations worldwide. Accordingly, the interest in marine derived Lyngbya species was growing, and became an essential source of chemical diversity with anti-infective effects. With regards to the source of the reported anti-infective compounds and as shown in Figure 33, it is clear that the morphotype Lyngbya is the main source of the compounds With regards to the source of the reported anti-infective compounds and as shown in Figure 33, it is clear that the morphotype Lyngbya is the main source of the compounds with 48 records (66%), followed by the morphotypes Moorea with 15 compounds (20%), Okeania with 9 compounds (10%) and Dapis with 3 compounds (4%) (Figure 33). Detailed contribution of the individual cyanobacterial morphotype is as follows: Dapis sp. As per the chemical diversity of the genus Lyngbya, it could be noticed that nitrogenous compounds represented as a predominant class of reported secondary metabolites with 59 nitrogenous compounds (83%) and 12 non-nitrogenous compounds (17%). This existence of these enormous nitrogenous secondary metabolites could be attributed to the capability of the members of cyanobacteria of fixing atmospheric nitrogen. Peptides are represented by 71% (51 compounds) from the nitrogen-containing secondary metabolites, while regular nitrogenous compounds, including alkaloids and others are represented by 9 compounds (12%) (Figure 34). Interestingly, there are 14 halogenated compounds among the reported anti-infective secondary metabolites.
Okeania with 9 compounds (10%) and Dapis with 3 compounds (4%) (Figure 33). Detailed contribution of the individual cyanobacterial morphotype is as follows: Dapis sp. (3 compounds), Lyngbya sp. (5 compounds), Lyngbya confervoides (3 compounds), Lyngbya lagerheimii (one compound), Lyngbya majuscula (37 compounds), Lygnbya polychora (2 compounds), Moorea bouilloni (4 compounds), Moorea producens (8 compounds), Okeania sp. (4 compounds and finally Okeania hirsuta (3 compounds) ( Figure 33). As per the chemical diversity of the genus Lyngbya, it could be noticed that nitrogenous compounds represented as a predominant class of reported secondary metabolites with 59 nitrogenous compounds (83%) and 12 non-nitrogenous compounds (17%). This existence of these enormous nitrogenous secondary metabolites could be attributed to the capability of the members of cyanobacteria of fixing atmospheric nitrogen. Peptides are represented by 71% (51 compounds) from the nitrogen-containing secondary metabolites, while regular nitrogenous compounds, including alkaloids and others are represented by 9 compounds (12%) ( Figure 34). Interestingly, there are 14 halogenated compounds among the reported anti-infective secondary metabolites.  As per the chemical diversity of the genus Lyngbya, it could be noticed that nous compounds represented as a predominant class of reported secondary me with 59 nitrogenous compounds (83%) and 12 non-nitrogenous compounds (17 existence of these enormous nitrogenous secondary metabolites could be attribute capability of the members of cyanobacteria of fixing atmospheric nitrogen. Pept represented by 71% (51 compounds) from the nitrogen-containing secondary met while regular nitrogenous compounds, including alkaloids and others are represe 9 compounds (12%) (Figure 34). Interestingly, there are 14 halogenated com among the reported anti-infective secondary metabolites. Most Lyngbya-derived compounds have demonstrated excellent antibacterial and antiprotozoal activities against different pathogens and parasites. Out of the 72 reported secondary metabolites from Lygnbya morphotype, 31 compounds (about 40%) have been reported to possess antiparasitic activities. In addition, 28 compounds (36%) of the reported compounds displayed antibacterial effects. With antifungal effects, the number was much less with only 12 compounds (15%). Finally, 3 compounds contributed to molluscicidal activity, 2 compounds for each of the antiviral and anti-diatom effects ( Figure 35). tiprotozoal activities against different pathogens and parasites. Out of the 72 repo ondary metabolites from Lygnbya morphotype, 31 compounds (about 40%) have ported to possess antiparasitic activities. In addition, 28 compounds (36%) of the r compounds displayed antibacterial effects. With antifungal effects, the number w less with only 12 compounds (15%). Finally, 3 compounds contributed to mollu activity, 2 compounds for each of the antiviral and anti-diatom effects (Figure 35

Conclusions
Herein, 72 compounds, mostly peptides, derived from different Lyngbya mor are described. To the best of our knowledge, the anti-infective compounds in thi showed significant activities, including antibacterial, anti-swarming, ant-quorum antifungal, antiparasitic, antiviral and molluscicidal activities. Therefore, membe genus Lyngbya morphotype represent a therapeutic gold mine of chemically and cally diverse natural products that exhibit a wide array of anti-infective effects. T tion of these chemical compounds over the span of more than forty years and t pounding evidence collected from biological and pharmacological investigation port of the compounds' pharmaceutical potential makes this intriguing cyanobac significant target for biomedical research and novel drug leads development. Th special attention should be given to the original source of such compounds when ing for medically or environmentally useful natural products. Therefore, a poten to drug development from the marine cyanobacterium Lyngbya would be the optim of its cultivation in the laboratory under the condition which would optimize the tion of the desired biologically active metabolites. Due to the special supplies, w required not only for cyanobacterial growth but also for the optimization of the tion of cyanobacterial secondary metabolites, broad efforts are worried with proach.
In summary, members of the Lyngbya morphotype have been exceptional so biosynthetic and biochemical novelty applied to drug discovery. Even facing sig headwinds, new discoveries from Lyngbya morphotype continue apace.

Conclusions
Herein, 72 compounds, mostly peptides, derived from different Lyngbya morphotype are described. To the best of our knowledge, the anti-infective compounds in this review showed significant activities, including antibacterial, anti-swarming, ant-quorum sensing, antifungal, antiparasitic, antiviral and molluscicidal activities. Therefore, members of the genus Lyngbya morphotype represent a therapeutic gold mine of chemically and biologically diverse natural products that exhibit a wide array of anti-infective effects. The isolation of these chemical compounds over the span of more than forty years and the compounding evidence collected from biological and pharmacological investigations in support of the compounds' pharmaceutical potential makes this intriguing cyanobacterium a significant target for biomedical research and novel drug leads development. Therefore, special attention should be given to the original source of such compounds when searching for medically or environmentally useful natural products. Therefore, a potential way to drug development from the marine cyanobacterium Lyngbya would be the optimization of its cultivation in the laboratory under the condition which would optimize the production of the desired biologically active metabolites. Due to the special supplies, which are required not only for cyanobacterial growth but also for the optimization of the production of cyanobacterial secondary metabolites, broad efforts are worried with this approach.
In summary, members of the Lyngbya morphotype have been exceptional sources of biosynthetic and biochemical novelty applied to drug discovery. Even facing significant headwinds, new discoveries from Lyngbya morphotype continue apace.