Introduction

Microbes are the prodigious contributors to the health of people worldwide as they serve as a prolific source of bioactive secondary metabolites. The microbial drug era started from the discovery of penicillin, discovered by Alexander Fleming. However various evidences witnessed that exposure to antibiotics is not confined to modern era but also existed during ancient era, knowledge regarding use of microbial drugs in ancient era is lacking. For example dating back to 350–550 CE from ancient Sudanese Nabia, tetracycline was found in human skeletal remains in trace amount [1, 2]. Similarly Cook et al.,1989 found antibiotic traces during histological analysis of femoral midshaft samples of late Roman period skeletons from Egypt [3].

Paul Ehrlich and Alexander Fleming did the pioneer work in utilizing microbes for drug production in 1929. Ehrlich’s systematic screening program is considered as a milestone in drug search approaches. These discoveries led to initiation of a new era in medicine “The Golden Age of Antibiotics” and since then production of some of the products of pharmaceutical value started for example, antibacterial agents such as penicillins (from Penicillium species), immunosuppressive agents such as cyclosporins (from Trichoderma sps.) antihelmintics and antiparasitic drugs such as the ivermectins (from Streptomyces sps.) [1]. Thus it can be concluded that these microbial secondary metabolites can serve as successful source of potential drug leads. The number of natural compounds discovered is more than 1 million. Among these natural compounds 50–60% is contributed by plant secondary metabolites such as alkaloids, flavonoids, terpenoids, steroids, carbohydrate etc. whereas 5% is contributed by microbial secondary metabolites [2].

Moreover, major work in identifying microbial drugs is restricted to chemoheterotrophs. Various other groups need attention so as to explore their potential as source of drug. Cyanobacteria, a diverse group of prokaryotic organism are capable of growing under diverse nutrient conditions, photoautotrophically, photoheterotrophically or chemoheterotrophically. Additionally, they are acquiescent to controlled fermenter studies. Thus above mentioned properties qualify them as a novel source of bioactive compounds and emerging as hot resource for drug search.

Besides, limited effective life span of antibiotics and public awareness toward overprescription and misuse of antibiotics are some other reasons that are drawing attention of clinical microbiologist towards cyanobacterial antimicrobial compounds. Further their survival in extreme environments, such as soda lakes (Spirulina, Cyanospira), cold and dry polar deserts (Chroococcidiopsis) and thermal springs (Synechococcus) requires exclusive metabolites that are not present in either higher plants or other microorganism. In addition, another advantage of cyanobacteria as a microbial source for drug discovery is reflected in terms of their economical cultivation as compared to other microorganisms due to their requirement of simple inorganic nutrients for growth.

The non-ribosomal polypeptide (NRP) or hybrid polyketide-NRP biosynthetic pathways can create cyanobacterial metabolites, which exhibit fascinating and diverse biological activity. Their structural types include significant subgroups of naturally occurring substances with therapeutic properties, such as the antibiotic vancomycin, the immunosuppressant cyclosporine, the chemotherapeutic medication bleomycin, and the histone deacetylase inhibitors largazole and santacruzamate A [4,5,6]. Various techniques are employed for extraction, isolation and purification of these cyanobacterial bioactive metabolites. Interestingly some of these have efficaciously reached to phase II and phase III of clinical trials.

Although various reviews have nicely summarized the cyanobacterial drugs and classified them on the basis of their biological activity. In present review, an effort is made to categorize cyanobacterial compounds on the basis of their chemical functional group.

Major functional groups of antimicrobial compounds from cyanobacteria

Figure 1 represents a flow chart portraying secondary metabolites from cyanobacteria which have been further described below.

Fig. 1
figure 1

Flow chart showing cyanobacterial metabolites

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Terpenes & terpenoids

Terpenes have general chemical structure C10H16, and they occur as diterpenes, triterpenes, and tetraterpenes (C20, C30, and C40), as well as hemiterpenes (C5) and sesquiterpenes (C15). When the compounds contain additional elements, usually oxygen, they are termed terpenoids. Nostoc commune produces an antimicrobial compound noscomin [7], a diterpenoid [8] and is active against Bacillus cereus, Staphylococcus epidermidis, and Escherichia coli, when compared against standard drug. Scytoscalarol [9] and cybastacines A and B [10] are sesquiterterpenes bearing a guanidinium or a guanidino group and were isolated from Scytonema and Nostoc, respectively.

Alkaloids

Alkaloids are nitrogen molecules that are heterocyclic. Many alkaloids have a well-defined pharmacological profile and are mostly employed in clinical treatments, ranging from analgesics to chemotherapeutics. Alkaloids stand out from all other varieties of natural substances by having a huge structural diversity and no predictable distribution [11]. Morphine, discovered in 1805 from the opium plant Papaver somniferum, was the first medically valuable alkaloid; the term morphine originates from the Greek Morpheus, God of sleep [12]. Hapalindoles, an indolealkoid produced by Hapalosiphon fontinalis [13] exhibit antibacterial antifungal properties. Hapalindole-type alkaloids, ambiguine isonitriles, exhibiting fungicidal activity, are produced by cyanobacterial species Fischerella ambigua, Hapalosiphon hibermicus and Westiellopsis prolific [14]. Fischerella muscicola, a terrestrial cyanobacterium, has been shown to produce fischerindole L, an antifungal molecule that is chemically linked to hapalindoles [15]. Nagatsu et al., 1995 [16] reported the production of antibacterial muscoride A, an oxazole peptide alkoid produced from Nostoc muscorum. Apart from the above mentioned compound, an alkaloid isolate, nostocarboline, isolated from Nostoc sp. found to be active against Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum [17]. Nostocarboline is also a powerful cholinesterase inhibitor, an enzyme that is used to treat Alzheimer’s disease [18]. The antifungal compounds tjipanazoles, which are chemically indolocarbazoles, have been isolated from Tolypothrix tjipanasensis [19]. Scytonema mirabile produces didehydromirabazole which possess antibiotic and cytotoxic activity [20]. Cylindrospermum licheniforme and Cylindrospermopsis raciborskii produces alkaloids cylindrocyclophane and cylindrospermopsin which are anticancerous and cytotoxic in nature, repectively [21, 22]. Moreover, cylindrospermopsin exhibited promising inhibitory potential against the SARS-CoV-2 MPRO (main protease) [23]. Moderate antibacterial activity has been showed by Nostoc sp. CAVN 10 against Staphylococcus aureus by the production of paracyclophane called carbamidocyclophane [24]. Caldora penicillata produce laucysteinamide A, a new hybrid thiazoline-containing alkaloid that was a monomeric homologue of the disulfide-bonded dimeric molecule somocystinamide A. Human non-small cell lung cancer H-460 cells were moderately cytotoxic by this substance [25]. Carriebowlinol, also known as 5-hydroxy-4-(chloromethyl)-5,6,7,8-tetrahydroquinoline, was discovered in an extensive cyanobacterial mat that was recovered from the coral reef at Carrie Bow Cay in Belize. Dendryphiella salina, Lindra thalassiae, and Fusarium sp. were all susceptible to carriebowlinol’s potent anti-fungal effects. Additionally, this substance showed strong anti-bacterial activity against Vibrio sp. [26].

Carbohydrates

Carbohydrates has been identified as another source of antimicrobial compound. Nostoc flagelliforme is known to produce nostoflan, an antiviral acidic polysaccharide, having virucidal activity against HSV-1, HSV-2, human cytomegalovirus and influenza A virus [27]. Apart from nostoflan, Calcium spirulan (Ca-SP), a natural sulphated polysaccharide, from Spirulina platensis, which selectively inhibits the penetration of virus into host cells has been reported to show broad range spectrum activity against various enveloped viruses, such as HIV-1, HSV-1, measles virus, mumps virus, influenza A virus and human cytomegalo virus [28]. Polysaccharides are thought to be helpful in treating human coronavirus infections because they have potent antifibrotic effects in the pulmonary tissues. It was shown that the polysaccharides generated from various Spirulina species, particularly Spirulina platensis, had unique antiviral efficacy against various enveloped viruses. In comparison to the industry standard dextran sulphate, Hayashi assessed the antiviral potential of calcium-spirulan produced from Spirulina platensis against HIV-1 and HSV-1. After 24 h of calcium-spirulan treatment, serum samples from the mice models demonstrated persistent antiviral action; nevertheless, their involvement in COVID-19 (SARS-CoV2 infections) is still limited [29, 30].

Phenolics and polyphenols

A single substituted phenolic ring makes up some of the most basic bioactive phytochemicals. In Cyanobacteria, Phormidium ectocarpii produces heirridin (2,4-dimethoxy-6-heptadecyl-phenol) which has been reported to possess antiplasmodial and antibiotic activity [31].

Fatty acid

The presence of an amide bond in a fatty acid chain and, in some situations, the incorporation of halogen atoms makes fatty acid amides one of the usual lipophilic class of chemicals. Omega-3 fatty acids, like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in abundance in cyanobacteria are known to prevent inflammatory cardiovascular illnesses [32]. Antibacterial compounds identified from the marine cyanobacterium Lyngbya majuscula are malyngamides which are amides of the fatty acid and 7(S)-methoxytetradecenoate [33]. Mundt, et al., [7] reported the presence of fatty acid from cyanobacterium Oscillatoria redeki HUB051 which showed antibacterial properties against B. subtilis SBUG 14, Micrococcus flavus SBUG 16, S. aureus SBUG 11 and S. aureus ATCC 2592. Phormidiun tenue shows anti HIV activity by the production of fatty acids [34]. Sulfoglycolipid which inhibit reverse transcriptase activity of HIV is produced from Scytonema sp. [35]. Antibiotic activity has also been shown by production of linolenic acid from Synechococcus sp. [36].

Polyketides

Cryptophycin, first discovered as a fungicide from a Nostoc strain in 1990, is the most well-known member of a cyanobacterial product with powerful anticancer effects. It is made up of a polyketide fragment, a modified D-α-amino acid, a β-amino acid, and a hydroxyl acid, making a depsipeptide, which is typical of cyanobacterial metabolites. It has powerful cytotoxicity against tumor cell lines [37]. The major protease Mpro and the papain-like protease PLpro, two SARS-CoV2 proteases, were used in the study to evaluate the molecular docking of the drugs at their binding pockets. These proteases are crucial targets for the creation of antiviral medications. The depsipeptide cryptophycin 52, one of the cyanometabolites, displayed encouraging results on the two SARS-CoV2 proteases [38]. Moore and coworkers discovered boron-containing polyketide borophycin from Nostoc linckia and later Nostoc spongiaeforme in 1994, against conventional cancer cell lines, this compound showed promising anticancer activity [39, 40]. The crude extract of Trichodesmium thiebautii was used to create the linear polyketide trichopycin A (56), which contains vinyl chloride. Both neuro-2 A cells and HCT-116 cells were moderately cytotoxic to trichopycin A [41]. In 2014, Trichodesmium erythraeum from Singapore was used to create two novel polyketides that are analogues of aplysiatoxin: 3-methoxyaplysiatoxin and 3-methoxydebromoaplysiatoxin. Infected SJCRH30 cells were post-treated with 3-methoxydebromoaplysiatoxin, which demonstrated substantial efficacy against the Chikungunya virus [25].

Peptides and proteins

In 1942, peptides that inhibit bacteria were discovered for the first time [42]. They’re usually positively charged and have disulfide bonds in them. The development of ion channels in the microbial membrane or competitive suppression of microbial protein adhesion to host polysaccharide receptors could be their mechanism of action [43]. Cyanobacteria have previously yielded many structural groups of peptides, including linear peptides, linear depsipeptides, linear lipopeptides, and cyclic peptides, cyclic depsipeptides, and cyclic lipopeptides [44]. Notably, certain cyanobacterial peptides and associated hybrid metabolites have even advanced as lead molecules for therapeutic use. For instance, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (trade name Adcetris), a medication derived from marine peptides, in 2011 for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma [45].Malyngamides are a type of linear lipopeptide that has become a hallmark of marine cyanobacterial secondary metabolism [46]. Since 2001, five further compounds [malyngamides S to W] have been found, bringing the total number of such molecules isolated from Lyngbya sp. to 34. Malyngamides T and U–W were obtained from a Puerto Rican and a Papua New Guinea collection of L. majuscula, respectively [47]. Dragomabin, a linear peptide isolated from Moorea producens with antiprotozoal activity against P. falciparum [48]. Dolastatin 10, a cyanobacterial metabolite, isolated from Symploca sp. [49], is a pentapeptide containing four unique amino acids, dolavaline, dolaisoleucine, dolaproline and dolaphenine and is a potent antiproliferative agent and acts by binding to tubulin on the rhizoxin-binding site, affecting microtubule assembly. Thus, arresting the cell into G2/M phase. Wrasidlo et al.,2008 [50], isolated Somocystinamide A (ScA) from Moorea producens, is a lipopeptide which is pluripotent inhibitor of angiogenesis and tumor cell proliferation and functions by inducing apoptosis in tumour and angiogenic endothelial cells. Antimicrobial activity has been found for a variety of cyclic peptides and depsipeptides isolated from cyanobacteria. These include tenuecyclamides which are antibacterial and cytotoxic agents isolated from the lithophytic cyanobacterium Nostoc spongiaeforme var. tenue [40], schizotrin A, an antifungal and antibacterial compound from Schizothrix sp. [51], hormothamnins (antibacterial and antifungal compounds) from the marine cyanobacterium Hormothamnion [52]. Ickthyopeptins A and B, cyclic depsipeptides isolated from the cyanobacterium Microcystis ichthyoblabe, have antiviral action against the influenza A virus [53]. Apratoxin A, a cyclodepsipeptide isolated from a Moorea sp. is cytotoxic to human tumor cell lines [54] by inducing the arrest of G-1 phase cell cycle and apoptosis [55]. Calothrix fusca [56] and Tolypothrix byssoidea [52] produces calophycin and tolybyssidins, respectively, which are antifungal in nature. Laxaphycins from Anabaena laxa [57, 58], majusculamide C from Moorea producens [59] possess both antifungal and antibacterial properties. Carbohydrate binding protein, Cyanovirin-N, isolated from Nostoc ellipsosporum, exhibits antiviral activity, it has been found to be a potent anti-HIV and it inhibit the HIV activity by binding to its gp 120, a surface envelope glycoprotein and further inhibiting the fusion of virus with the cellular receptor CD4 [60]. Cyanovirin-N was identified with the S glycoprotein of SARS-CoV-2 and was found to have the highest concentration among other lectins using molecular docking and MD simulation experiments. Lokhande demonstrated that binding complexes between BanLec in its wild-type and mutant forms are more thermodynamically stable [61]. Scytovirin, another carbohydrate binding protein isolated by Bokesch et al., 2003 [62] from aqueous extract of Scytonema variumis a potent anti-HIV protein that acts by binding to viral coat proteins gp120, gp160 and gp41. The Panamanian International Co-operative Biodiversity Group has reported the isolation of antiprotozoal compounds from cyanobacteria. Viridamide A isolated from Oscillatoria nigro Virdis, is active against Trypanosoma cruzi, Leishmania mexicana, Plasmodium falciparum[63]. Aerucyclamide C and aerucyclamide B (heterocyclic ribosomal peptide) isolated from Microcystis aeruginosa PCC 7806 is active against T. brucei and P. falciparum, respectively [64].

Discussion

Cyanobacteria are cosmopolitan, oxygenic photosynthetic bacteria and are found in diverse habitat. They have been recognised recently for their potential to produce therapeutic compounds. Present review article compiled therapeutic potential of cyanobacterial metabolites in terms of chemical functional group (Table 1). Moreover, it has also been reported that many of them are capable of producing more than one kind of metabolite with same functional group which either act against wide spectrum of microbes or act on single microbe (Fig. 2). Though much research has been done to extract various metabolic compounds possessing antimicrobial activity using numerous procedures and protocols but further research is needed in this field for proper understanding of action mechanism as very few cyanobacterial metabolites have entered clinical trials and till date only brentuximab vedotin (trade name Adcetris), a medication derived from marine peptides, for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma has been approved by FDA (Food and Drug Administration). Therefore, the field of phycochemistry requires more intensive and interdisclipinary research and many clinical trials need to be take place in order to establish them as a source of antimicrobial agent or anti cancerous agent. Moreover, there is need to explore cyanobacteria as therapeutic agent in order to produce alternative source of drugs because it is cost effective as cyanobacteria is easy to maintain in culture condition due to its ability to harbour in simple inorganic nutrient condition and many of them show wide spectrum activity against microbes.

Fig. 2
figure 2

Anti-microbial activity of cyanobacteria. A Anti-cancerous and anti-microbial activity of cyanobacterial metabolites possessing same functional group. *Metabolites. B Wide antimicrobial activity of cyanobacterium producing different metabolites with same chemical functional group

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Table 1 Classification, structure of various cyanobacterial metabolites possessing antimicrobial activity
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Conclusion

The review article compiled therapeutic potential of cyanobacterial metabolites in terms of phycochemistry. Cyanobacterial metabolites display fascinating and broad bioactivity and numerous techniques are employed for extraction, isolation and purification of these cyanobacterial bioactive metabolites. However, most of the research has been focused on model organisms such as Synechocystis sp. PCC 6803 and Anabaena PCC7120 particularly towards abiotic stress-induced modifications of gene and protein expression such as response to salinity, UV-B, heat, high light intensities and nutrient deprivation etc. Another field that is much studied is engineering of cyanobacteria for biofuel production. Nevertheless, taking recourse to pharmaceutical importance of cyanobacterial metabolites, more attention is needed to explore cyanobacteria as a source of therapeutic compound to find more novel antimicrobial compound and to fully understand the mechanisms of action linked to cyanobacterial metabolites, additional in vivo research is still required. For instance, nostoflan showed strong antiviral efficacy against type 1 of the herpes simplex virus (HSV-1). The broad-spectrum antiviral calcium spirulan supplement has an effect on the reduction of human viruses’ ability to replicate in vitro, including HCMV, HSV-1, HHV-6, and HIV-1. Together, these signs suggest that cyanobacterial products may play a role in the fight against coronaviruses, which calls for more research into testing cyanobacterial secondary metabolites against SARS-CoV-2 and in particular to combat the COVID-19 pandemic. Furthermore, cyanobacteria from unexplored and extremes of environment should also be studied in order to discover novel compounds.