A Review on Microorganisms-Derived Products as Potential Antimicrobial Agents

Microorganisms including actinomycetes, archaea, bacteria, fungi, yeast, and micro algae are the auspicious source of vital bioactive compounds. In this review, the existing state of the art re-garding antimicrobial molecules from microorganisms has been summarized. The potential an-timicrobial compounds from actinomycetes, particularly Streptomyces sp.; archaea; fungi including endophytic and marine-derived fungi, mushroom; yeast, and microalgae were briefly described. Furthermore, this review briefly summarized the activity and mode of action of bacteriocins, a ribosomally synthesized antimicrobial peptides product of Eurotium sp., Streptomyces parvulus, S. thermophiles, Lactococcus lactis, etc. Bacteriocins have inherent properties such as targeting multi-ple-drug resistant pathogens, which allows them to be considered next-generation antibiotics. Similarly, Glarea lozoyensis derived antifungal lipohexpeptides i.e., pneumocandins, inhibits 1,3-β-glucan synthase of the fungal cell wall and acts as a precursor for the synthesis of caspo-fungin, is also elaborated. In conclusion, this review highlights the possibility of using microor-ganisms as an antimicrobial resource for biotechnological, nutraceutical, and pharmaceutical ap-plications. However, more investigations are still required to separate, purify, and characterize these bioactive compounds and transfer these primary drugs into clinically approved antibiotics.


Introduction
For the last few decades, antibiotics have saved millions of lives but the prevalence of multidrug resistance (MDR) microbial strains, nullifying the effects of antibiotics are the expected consequences of antibiotics abuse. The emergence and prevalence of antibiotic-resistant microbial strains remain one of the major health issues of the 21st century, creating selective pressure on natural microbiota. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are one of the greatest challenges in medical practices as most of them are multidrug-resistant isolates [1]. The US Centres for Disease Control and Prevention (CDC) classified the most concerning antimicrobial resistance (AMR) threats, cataloging carbapenem-resistant P. aeruginosa, Clostridium difficile, and A. baumannii; MDR Neisseria gonorrhoeae and carbapenem-and cephalosporin-resistant Enterobacteriaceae as "urgent" threats [2], requiring urgent measures to cope up the situation. Pendleton et al. [3] provide a contemporary summary and clinically relevant information on the ESKAPE pathogens. In contrast, the detailed description regarding the antimicrobial resistance mechanisms of ESKAPE pathogens was illustrated by Santajit and Indrawattana [1], which can be used as a tool and applied to emerging MDR pathogens. Mulani et al. [4] highlight the use of therapies, including the combination of antibiotics, bacteriophages, antimicrobial peptides, nanomedicines, and photodynamic light therapy to overcome the limitations of individual therapy. These advanced and combinatorial therapies could be used as an alternate solution to combat AMR.
Due to increased consumption of livestock products in middle-income countries, antimicrobial consumption will increase up to 67%, and up to two-fold in India, Brazil, China, Russia, and South Africa, by 2030 [5]. However, the approval of antibacterial agents decreased by 56 % from 1998 to 2002 as compared to the period from 1983 to 1987, and out of total 225 new molecular entities, only 3% of antimicrobial agents were approved by the United States Food and Drug Administration (FDA) from 1983 to 2002. FDA approved 6 novel antibacterial drugs, including the 3 rd generation cephalosporin and βlactamase inhibitor combination ceftazidime/avibactam, in 2015 [6], whereas in 2018 and 2020, not a single antimicrobial drug had been approved by FDA [7].
The current review summarizes the microbial metabolites, including growth hormones, pigments, antibiotics, etc., that have become significant sources for life-saving drugs. Many of these microbial metabolites hold specific antimicrobial potential and act at particular target sites ( Figure 1); thereby, they can be an attentive source for biotechnological applications, specifically for pharmaceuticals and nutraceuticals [8]. During the late 1980s, a shift from chemical synthesis of drug discovery from nature to the laboratory bench has taken place, resulting in the discovery of approximately 50 % natural drugs from 1981 to 2010 [9]. Prodigiosin, an antimicrobial pigment produced by the marine bacterium Vibrio ruber, induces autolytic activity in the Bacillus subtilis. Similarly, Lantibiotics from Gram-positive bacteria were bioengineered to increase their effectiveness against a wide range of bacterial strains and improve their stability while transmitting through the gastrointestinal (GI) tract making them protease-resistant [10].
Biofilms formed by bacteria are ubiquitous and are a part of their survival mechanisms. Biofilms have been involved in many clinical infections such as atherosclerosis, pharyngitis, laryngitis, pertussis, bacterial vaginosis, etc. [11]. Apart from causing deadly infections and diseases, bacterial antimicrobial compounds are reported as antifungal, antiviral, etc., as described in this review. We briefly highlighted the bacteriocins from lactic acid bacteria (LAB) and their mode of action. Most antimicrobials disrupt the cell membrane integrity or inhibit cell wall synthesis, protein, and nucleic acid synthesis. A recent study by Ting et al. [12] updated the epidemiology of the infectious keratitis (IK), the leading cause of corneal blindness; its causative microorganisms including bacteria, virus, fungi, parasites, and polymicrobial infections; major risk factors associated with IK and the impact of AMR on the treatment of IK. Antimicrobial compounds such as vinaceuline, bafilomycin, antimycin, and other anti-methicillin-resistant S. aureus (MRSA) compounds synthesized by Streptomyces sp., having antagonistic activity against different microbial strains are discussed in the present review. We also elaborated on the halocins and sulfolobicin from archaea. Further, the antimicrobials reported from endophytic and marinederived fungi along with mushrooms, yeasts, and microalgae are summarized. Microalgae act as a potential source of antimicrobial substances due to the synthesis of indoles, acetogenins, terpenes, phenols, and volatile halogenated hydrocarbons, which have also been discussed. Hence this review documented the potential antimicrobial compounds discovered from the all-possible microbial resources, including microbes inhabiting extreme habitats.

Bacteria
Bacterial antimicrobial compounds have been used traditionally for numerous reasons, including delaying the spoilage of food material or crops by plant pathogens in agriculture and extending the shelf life of products in the food industry [13]. Bacillus strains are well-acknowledged to produce extensive biocontrol metabolites, which include the ribosomally synthesized antimicrobial peptides (bacteriocins) [14], as well as non-ribosomally synthesized peptides (NRPs) and polyketides (PKs) [15].

Ribosomally synthesized antimicrobial peptides (bacteriocins) and bacteriocin-like inhibitory substances (BLIS):
Bacteriocins are antimicrobial ribosomal peptides reported from all major lineages of bacteria and some members of archaea. Gram-negative bacteria Escherichia coli produces colicins that are bacteriocidal protein, which is larger than 20 kDa and prevents the growth of closely related strains [16]. Bacteriocins have attracted more attention because of their impending use as a usual food preservative and therapeutic antibiotic. Another reason is that they have a rapid-acting mechanism by forming pores in the membrane of target bacterial cells, even at very low concentrations ( Figure 2). The recently reported bacteriocins along with their characteristics are presented in Table 1. Bacteriocins from lactic acid bacteria (LAB) have gained significant attention due to their food-grade quality and industrial significance. LAB and its by-products are generally regarded as safe (GRAS) as a human food component by the U.S. Food and Drug Administration (FDA). Hence it is safer to use LAB bacteriocin to constrain the growth of pathogenic/undesirable bacteria [17]. Lozo et al. [18] isolated the strain Lactobacillus paracasei from customarily homemade white-pickled cheese and reported that it produces bacteriocin 217 (Bac217), exhibiting antimicrobial activity against Pseudomonas aeruginosa, Bacillus cereus, Salmonella sp., and S. aureus.
A study by Drissi et al. [19] suggests that bacteriocins are widespread across the human GI tract, with 317 microbial genomes encoding maximum bacteriocins of classes I (44%) as compared to class II (38.6%) and III (17.3%). Further, they elaborated the bacteriocins produced by gut microbiota, i.e., Class I bacteriocins display low antimicrobial activity. Whereas maximum class II bacteriocins were reported from bacteria not occurring in the gut. Similarly, Leite et al. [20] described BLIS produced by Bacillus cereus LFB-FI-OCRUZ 1640, with activity against Listeria monocytoges and other Bacillus species in pineapple pulp and can be used as a potential food bio preservative. Also, Choeisoongnern et al. [21] reported that BLIS produced by Pediococcus pentosaceus, and Enterococcus faecium from fermented food inhibits the growth of Carnobacterium maltraromaticum, Candida albicans, Listeria ivanovii, Listeria innocula, Pseudomonasc aeruginosa, Streptococcus mutans, and S. aureus. More recently, Pircalabioru et al. [22] comprehensively reviewed bacteriocins' potential as an antimicrobial agent against infections mainly due to resistant pathogens i.e., MRSA. In contrast, Jawan et al. [23] suggest that BLIS from Lactococcus lactis Gh1 inhibits the growth of Listeria monocytogenes and can be used in the food industries as functional foods for the preparation of starter culture and probiotic products. In addition, BLIS from B. subtilis BSC35 inhibits Clostridium perfringens; therefore, it can be used to control C. perfringens in fermented foods [24].
Unfortunately, many factors cause a reduction in BLIS antimicrobial activity affecting the efficacy of bacteriocins. Such factors include the advent of bacteriocin-resistant strains, conditions that were destabilizing its biological activities such as oxidation processes, poor solubility, proteases or inactivation by other additives, and pH or temperature. Therefore, it is necessary to develop such a system that minimizes these drawbacks and maximizes bacteriocins' bioprotective potential.  [32] Nisin belongs to type I bacteriocin and is the first antimicrobial peptide from Lactococcus and Streptococcus sp. and has been regarded as GRAS by both FDA and WHO [33]. Nisin has been used to inhibit microbial growth in beef, ground beef, sausages, liquid whole eggs, and poultry. It was reported that when nisin was cross-linked to chitosan, minimum inhibitory concentration (MIC) decreased from 48 μg/ml to 40 μg/ml for Staphylococcus aureus ATCC6538. Antimicrobial activity of nisin was increased after crosslinking with a lesser concentration of chitosan i.e., the ratio of 200:1, thereby allowing better penetration into the lipid membrane [34]. The antibacterial constancy of nisin was successfully enhanced after its conjugation with gellan. The gellan-nisin conjugate was able to tolerate a broad range of pH and temperature, and also its antibacterial duration against Staphylococcus epidermidis was improved from 48 h to 144 h under alkaline environments and from 96 h to 216 h under acidic conditions. Therefore this conjugate can be an encouraging biomaterial for wound dressings and transplant coatings [35]. Heunis et al. [36] stated that the application of nisin-coated wound dressing prevented S. aureus' colonization and quickened the healing procedure. A study revealed the proficiency of nisin in combination with polymyxin in combating P. aeruginosa biofilms and reduced the dose of polymyxin required to interrupt P. aeruginosa biofilms [37]. Possibly polymyxin might facilitate the transfer of nisin to its target. Along with nisin's synergistic action with polymyxin and clarithromycin against P. aeruginosa and other non-β-lactam antibiotics against MRSA [38] and strains of vancomycin-resistant enterococci [39] was also reported. Webber et al.
[40] embedded 0.89 µg cm −2 , positively charged nisin Z within polyelectrolyte multilayers (PEMs) i.e., 9 layers of carrageenan (CAR) and chitosan (CS), forming a 4.5 bilayer film with antimicrobial activity against S. aureus and MRSA. Therefore, the antimicrobial potential of CAR/CS multilayers helps in realizing its applicability within food, pharmaceutical, and biomedical industries [40]. Apart from bacteria, nisin also inhibits fungal growth (i.e., Candida albicans). Though nisin has a broad range of biomedical applications and is used in food bio preservation yet further justification of nisin's practicality and evaluation of its efficacy in biomedical fields will require in vivo and in vitro studies.
Bacteriocins in Gram-positive bacteria follow two possible mechanisms, as shown in Figure 2. Class I bacteriocins are cationic lantibiotic (e.g., nisin) that electrostatically binds with the negatively charged membrane phospholipids II, allowing further interaction of bacteriocin's hydrophobic domain with the target cytoplasmic membrane (lipid II), thereby preventing the biosynthesis of peptidoglycan [22,[41][42].

Non-ribosomal synthesized peptides (NRPs) and polyketides (PKs):
NRPs and PKs include a range of cyclic, linear, and branched compounds, synthesized by composite enzymes viz. non-ribosomal peptide synthetases (NRPS), polyketide synthetases (PKS), and hybrid of NRPS/PKS, respectively [15,43]. Lipopeptides (LPs) are NRPs produced by Bacillales, have significant antimicrobial activity [44]. LAB is considered the primary producer of ribosomally synthesized antimicrobial peptides, as reviewed by Alvarez-Sieiro et al. [45] and Pircalabioru et al. [22]. However, the classification scheme for antimicrobial compounds produced by Bacillus is not explored as compared to LAB. Caulier et al. [15] reviewed and updated the antimicrobial metabolites classification from the B. subtilis group based on the biosynthetic pathway and chemical nature. Zhao et al. [14] acknowledged 31 types of PKs, NRPs, and NRPS/PKS hybrid synthesized antimicrobials using antiSMASH.

Lipopeptides (LPs):
LPs occur naturally and are of bacterial origin, contain a hydrophobic long alkyl chain that associates with a hydrophilic polypeptide, and forms a cyclic or linear structure [46]. Traditional LPs including the iturins, surfactins, and fengycins (Table 2) produced from Bacillus species and are homologs that differ in length, branching pattern, and saturation of their acyl chain. LPs comprise anionic (e.g., surfactin and daptomycin) or cationic (e.g., colistin and polymixin B) peptide motif, dictating the range of its activity.  Surfactins, a cyclic heptapeptide that formulates a lactone bridge with ß-hydroxy fatty acids, are the most potent biosurfactant. It displays an array of activities including hemolytic, antiviral, anti-mycoplasma, and antibacterial [52]. Surfactin WH1 fungin from Bacillus amyloliquefaciens WH1 is an antifungal inhibiting glucan synthase that reduces the synthesis of callose on the fungal cell wall and binds to ATPase on the mitochondrial membrane ultimately inducing apoptotic markers to stimulate the extracellular apoptotic pathway [53]. Many researchers claim that after inserting into the lipid bilayers, surfactin acts by forming voltage-independent channels in biofilms, distorting the membrane integrity and permeability of ions, i.e., K + and Ca 2+ , causing membrane disruption [54].
Iturins comprises A, C, D, and E isoforms, bacillomycin D, F and L, and mycosubtilin that inhibit bacterial growth in the same manner as Class I and Class II bacteriocins [55], whereas mycosubtilin modifies the plasma membrane permeability, thereby liberating nucleotides, proteins, and lipids from the cell [56]. A marine-derived Bacillus velezensis 11-5 produced a cyclic lipopeptide (CLP) iturin A, considered an antagonist against Magnaporthe oryzae, a rice pathogen [57].
Fengycin, an anti-fungal lipopeptide, isolated from Bacillus sp. is also called plipastatin. Its isoforms fengycin A and fengycin B vary in the single amino acid at the sixth position (D-alanine and D-valine, respectively) [58]. Both iturins and fengycins act as biocontrol agents preventing plant diseases and inhibiting the progression of a wide variety of plant fungal pathogens including Aspergillus flavus, Rhizoctonia solani, Fusarium graminearum, Botritis cinerea, and Penicillium expansum [59].
Kurstakins are cyclic heptalipopeptides [60], whereas cerexins are linear LPs [61], and both are isolated from Bacillus thuringiensis and Bacillus cereus respectively. Cerexins are active against S. aureus and Streptococcus pneumoniae [62]. Octapeptins, cationic peptides produced by Bacillus sp. and Paenibacillus sp., have antimicrobial activity, inhibiting filamentous fungi, yeasts, and protozoa along with some Gram-positive and Gram-negative bacteria by disrupting the cytoplasmic membrane [63].
However, no doubt LPs are a novel class of antibiotics exhibiting a wide range of activities. Therefore, detailed structural and functional knowledge is required to exploit these LPs as antibiotics, anti-tumor agents, antimicrobials, feed additives, and drug delivery systems.

Actinomycetes
The actinomycetes are Gram-positive, aerobic, filamentous, and spore-forming bacteria, with a foremost reputation for producing chemically different metabolites bearing a broad spectrum of biological activities, including antifungal, antibacterial, and insecticidal activities. Approximately 75% of the known industrial antibiotics and economically important compounds were obtained from the Streptomyces species [64]. Actinobacteria can synthesize antifungal, antiviral, antitumor, anti-inflammatory, antioxidants, immunosuppressive, plant-growth-promoting, and herbicidal compounds [65]. Among actinobacteria, Streptomyces is the utmost and dominant because of a broad range of bioactive metabolites. The genus Streptomyces alone contributes approximately 7500 compounds among the 10,000 known compounds from actinobacteria, whereas the other genera including Actinomadura, Micromonospora, Nocardia, Saccharopolyspora, Actinoplanes and Streptosporangium contributes approximately 2500 compounds [66]. Marine or terrestrial actinobacteria utilize enzymes polyketide synthases (PKS) or non-ribosomal peptide synthetases (NRPS) for the synthesis of metabolic bioactive compounds [67].
Lee et al. [75] isolated 87 actinobacterial species including a novel species Streptomyces pluripotens MUSC135T, that inhibit MRSA. This antibacterial metabolite-producing ability was confirmed by PKS (polyketide synthetase) and NRPS (non ribosomal polyketide synthetase) gene detection process. Streptomyces sp. colonizing on root tissues produce ample antifungal and antibacterial compounds i.e., antimycin A18, phaeochromycin B, C and E, diastaphenazine, 3-acetonylidene-7-prenylindolin-2-one, and staurosporine, some of them are represented in Table 3. The unique properties of rhizospheric actinomycetes to produce a diverse range of bioactive metabolites with antagonistic outcomes toward pathogens have led them to be a potent agent ensuring plant health.
Cycloserin, an antibiotic produced by Streptomyces orchidaceus, block protein synthesis and is used to treat tuberculosis in conjugation with other drugs [84]. Robertsen and Musiol-Kroll, [85] reviewed the actinomycetes-derived polyketide drugs such as erythromycin A, tetracyclines, rifamycin, tylosin, monensin A, amphotericin B, etc. with antimicrobial activity, including the source of the compounds, their structure, the biosynthetic mechanisms, and mode of action. However, the increasing rate of MDR requires the rediscovery of compounds from potential producers. However, many organisms require special cultivation conditions, so many strategies need to be developed to overcome such barriers. Hug et al. [86] described the strategies and innovative methods such as advanced cultivation methods, genomics, metabolomics, and metagenomics-based approaches to explore the new reservoir of actinomycetes and improve the efficacy of antimicrobial compounds. Table 3. Bioactive compounds from endophytic actinomycetes.

Archaea
Archaeocins, is a proteinaceous antibiotic produced from archaea and mark the chronicled beginning in the series of antimicrobial compounds. The term "archaeocin" was used to differentiate the archaeal peptide and protein-based antibiotics from those produced by bacteria [88]. Only two phylogenetic groups have produced Archaeocins (Table 4); one is euryarchaeal producing "halocins" whereas the other group is crenarchaeal genus Sulfolobus producing "sulfolobicin" [89]. Valera et al. [90] reported halocins, the first proteinaceous antimicrobial compound from halophilic members of the archaeal domain. Archaeal protein VLL-28, from Sulfolobus islandicus, is the first archaeal antimicrobial peptide, possessing a broad-spectrum antibacterial and antifungal activity [91]. Until now, very few reports were available on the characterization of antimicrobial compounds from archaea. Besse et al. [92] and his team comprehensively reviewed the Streptomyces sp. Diketopiperzines -Anti-H1N1 activity [83] archaeocins and sulfolobicins antimicrobial peptides ribosomally-synthesized by archaea belonging to the order Halobacteriales and Sulfolobales, respectively. However, till now halocin A4, G1, R1, H1 [93]; H2 [29]; H3, H5 [90]; H4 [94]; H6 [95]; C8 [96]; S8 [97]; HalR1 [98]; and Sech7a [99] have been considered up to their molecular level, still their mode of action is not clearly understood [100]. Only some workers reported that halocins kill the indicator organisms by altering the cell permeability at membrane level followed by cell lysis. However, to date, only the mode of action mechanism of halocin H6/H7 produced by Haloferax gibbonsii was characterized. HalH6 specifically inhibits Na + /H + antiporter and proton flux ultimately causing cell lysis and death [101]. H1 and H4 are proteinaceous halocins of roughly 30-40 kDa [102], whereas C8, H6, H7, R1, U1, and S8 are microhalocins of size smaller than 10kDa. Microhalocins are more vigorous than proteinaceous halocins since they are resistant to flexibility in temperature, salinity, exposure to organic solvents, acids, and bases [102]. Halocins have a wide-ranging activity against haloarchaea and members of the family Halobacteriaceae [103]. Mainly halocin production is prompted during the progression between exponential and stationary phases, with H1 being an exception, produced during the exponential phase of the growth cycle [104]. Recently, Sahli et al. [105] screened 81 halophilic strains collected from solar salterns of Algeria's northern coast for the production of antimicrobial compounds. Through partial 16S rRNA gene sequencing, these strains were recognized to belong to the Haloferax (Hfx) sp. ND [109] Note: ND: Note Detected or Not Reported.
Roscetto et al. [110] reported that VLL-28 damages the cell wall of Candida albicans and C. parapsilosis by binding to their cell surface. Kumar and Tiwari [111] purified halocin HA1 from Haloferax larsenii HA1 and HA3 from H. larsenii HA3; both were halocidal against H. larsenii HA10, instigating cellular distortion, releasing cell contents, and finally causing cell death. Because of these properties, it can be used for the preservation of leather hides and salted foods in the leather and food industries. Ghanmi et al. [107] isolated Halobacterium salinarum ETD5, H. salinarum ETD8, and Haloterrigena thermotolerans SS1R12 of the order Halobacteriales and reported that their antimicrobial activity is due to the production of a halocin, HalS8, a hydrophobic peptide. Quadri et al. [112] isolated archeal strain Natrinema gari, the common producer of antimicrobial compounds, which after partial purification and characterization resembles the microhalocin HalC8. Besse et al. [108] confirmed that Natrinema sp. synthesizes Halocin C8, a 7.4 kDa peptide involving the genes halC8.
Although many studies characterized the synthesis of halocins however the research concerning their structure and mode of action is still far behind compared to the antibiotics produced by other domains. Nowadays, when archaea gain more attention, it becomes necessary to explore their metabolites' biosynthesis, including haloarcheocins and sulfolobicins, using the latest available technology and interdisciplinarity.

Fungi
In 1929, Alexander Fleming discovered that mold juice 'Penicillin' from Penicillium notatum fungus with an antibacterial activity [113]. Afterwards, several researchers started to find out for a better strain to attained higher yield in easier growth conditions. After the extensive research Penicillium chrysogenum strains considered for commercial production of Penicillium [114]. Revilla reported in 1986 that the formation of the intermediate isopenicillin N in the course of penicillin G production in P. chrysogenum cultures [115], while thereafter the formation of isopenicillin N/penicillin N and its late transformation to cephalosporin C in Acremonium chrysogenum [116]. Cephalosporins, a known antimicrobial agent were purified from a marine fungus, Cephalosporium acremonium [117]. Recently, Li et al [118] reported that pneumocandins, a lipohexapeptides of the echinocandin family, were produced by wild-type fungi Glarea lozoyensis and Pezicula (Cryptosporiopsis) species. Pneumocandins non-competitively bind to a catalytic unit of β-1,3-glucan synthase resulting in osmotic uncertainty and cell lysis.

Endophytic fungi
Huang et al.
[119] discovered ten membered lactones from endophytic fungus Phomopsis sp. YM 311483, with antifungal activity against Aspergillus niger, Fusarium, and Botrytis cinere. Endophytic Fusarium sp. from Selaginella pollescens collected from the Guanacaste conservation area of Costa Rica inhibit Candida albicans [120]. The number of antimicrobial compounds was reported from the endophytic fungi, some of which are listed in Table 5.

Marine-derived fungi
Meng et al. [126] in 2015 discovered pyranonigrin F from fungus Penicillium brocae MA-231 allied with the Avicennia marina, a marine mangrove plant. Pyranonigrin F inhibits S. aureus (Gram-positive), Vibrio harveyi, and Vibrio parahemolyticus (Gram-negative bacteria), with considerably lower MIC values as compared to the positive control (chloromycetin). Likewise, it is active against plant fungal pathogens Alternaria brassicae and Colletotrichum gloeosprioides, with improved MIC values compared to the positive control (bleomycin). Wu et al. [127] discovered Lindgomycin from Lindgomyces strains LF327 and KF970, reported from a sponge in the Baltic Sea, Germany, and Antarctica, respectively. Lindgomycin displayed antimicrobial activity against S. aureus, S. epidermidis, and methicillin-resistant S. epidermidis (MRSE). However, the inhibiting potential was two times lesser as compared to the positive control chloramphenicol. It also constrains plant pathogenic bacterium Xanthomonas campestris. There is a never-ending list of antimicrobial compounds from marine fungi; a few of them are listed in Table 6, mentioning their host, producer species, and bioactivity.

Colletotrichum asianum
Marine sponge Callyspongia sp. [148] Peniciadametizine A and Peniciadametizine B derivative of thiolated diketopiperazine was isolated from a sponges-associated Penicillium sp. viz. Penicillium adametzioides AS-53 and Penicillium sp. LS54 respectively. Both derivative inhibits Alternaria brassicae (pathogenic fungus) with a MIC of 4.0 μg/mL and 32.0 μg/mL respectively [131]. Communol A, G, and F extracted from P. commune 518 displayed antibacterial activities against E. coli with MIC values of 4.1, 23.8, and 6.4µM, respectively, and also against E. aerogenes [129]. Pyrrospirones were produced by marine-derived fungus Penicillium sp. ZZ380, isolated from Pachygrapsus crassipes which is a wild crab found on the seaside rocks of Putuo Mountain (Zhoushan, China). Pyrrospirones C-F, H, and I inhibit MRSA and E. coli having MIC values of 2.0-19.0 μg/mL [149]. Song et al. [150], following the previous lead, separated penicipyrrodiether A from a cultured marine fungal strain Penicillium sp. ZZ380 inhibits E. coli and S. aureus with MIC of 34.0 and 5.0 μg/mL, respectively. These laboratory studies need to be directed toward enlightening the efficiency and effectiveness of isolated compounds that could benefit society in the long-run.

Mushroom
Mushrooms are colonizing fungi belonging to division Eumycota and subdivision Basidiomycetes, characterized by the formation of basidiospores. Most of these macrofungi are edible, with culinary, nutritional, and medicinal characteristics, but many of them are not palatable or poisonous [151]. Besides the nutritional and culinary properties, their antimicrobial activities attracted people seeking natural solutions to cope with the urgent requirement for food safety. Mushrooms have been publicly consumed for thousands of years due to their medicinal and nutritional properties. Secondary metabolites and extracts from mushrooms have recently attained considerable attention due to their anti-cancer, antioxidant, anti-inflammatory, antimicrobial, antidiabetic, and immunomodulatory activities. Approximately 1069 mushroom species have been consumed by people [152]. Till today, numerous antimicrobial peptides have been acknowledged from mushrooms. Plectasin (endogenous peptide antibiotics), an antibacterial peptide, was extracted from Pseudoplectania nigrella. Mygind  of recombinant plectasin against some Gram-positive Streptococcus pneumoniae. Wong et al. [154] described an antifungal peptide, cordymin isolated from medicinal mushroom Cordyceps militaris, which repressed mycelial growth of Bipolaris maydis, Mycosphaerella arachidicola, Candida albicans, and Rhizoctonia solani with IC50 values of 50 μM, 10 μM, 0.75 mM, and 80 μM respectively. They also reported the remarkable pH stability (pH 6-13), thermostability (100 °C), and metal ion stability (10 mM Mg 2+ and 10 mM Zn 2+ ) of cordymin. An investigation by Gebreyohannes et al. [155] revealed that chloroform, ethanol, and hot water extract of Auricularia and Termitomyces sp. promisingly inhibited E. coli, K. pneumoniae, C. parapsilosis, and S. aureus. Poompouang and Suksomtip, [156] isolated an antifungal compound of 17 kDa from fruiting bodies of edible mushroom Lentinus squarrosulus, inhibiting Trichophyton mentagrophytes and T. rubrum, a human fungal pathogen. More recently, Irshad et al. [157] comprehensively reviewed the synthesis and action mechanism of polysaccharides silver nanoparticles (NPs) from Pleurotus mushroom. They characterized the NPs through ultraviolet-visible (UV-Vis), Fourier transformation infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM), etc. and disclosed their promising antimicrobial efficiency. However, further studies are required to fortify and test these extracts and NPs against human and plant pathogenic microbes coupled with the purification and characterization of the compounds from mushroom. Hamamoto et al. [158] screened the volatile compound, 3,4-dichloro-4-methoxy benzaldehyde (DCMB) from mycelia of Porostereum spadiceum. It remarkably inhibited the plant-pathogenic bacteria (Clavibacter michiganensis and Ralstonia solanacearum) and inhibit the conidial germination of plant-pathogenic fungi (Alternaria brassicicola and Colletotrichum orbiculare). However, further studies are essential to investigate its effects on plant-pathogens in vivo. Subrata et al. [159] reported that edible wild mushrooms' methanolic extracts exhibited different levels of antimicrobial activities. A recent work by Sevindi [160] analysed the phenolic content of the wild edible mushroom Melanoleuca melaleuca (Pers.) Murrill had antimicrobial activities inhibiting Gram-negative E. coli, Pseudomonas aeruginosa, and Acinetobacter baumannii.

Yeast
Yeasts mainly occur in milk, meat, food, and products such as fruit, yogurt, jams, sausage, and cheeses. Generally, antimicrobial compounds produced from yeasts inhibit the evolution/growth of pathogenic organisms (bacteria or molds) in food products. Some classes of yeasts secrete toxins, thereby naming them killer yeasts. Killer yeasts naturally occur in rotten vegetables and fruits and constrain the growth of other yeast strains and also inhibit microbial growth [161]. Saccharomyces cerevisiae (Baker's yeast), unicellular yeast, is the most widely studied microorganisms involved in many biotechnological practices because of its good fermentation capacity [162]. The inhibitory mechanism of S. cerevisiae killer strains was discovered in 1963 by Bevan and co-worker's, and the phenomenon is related to the secretion of a protein toxin, k1, and k28 from the host that kills sensitive target pathogenic cells in a receptor-mediated approach without direct cell-to-cell contact [163]. Other genera producing killer toxins include Cryptococcus, Candida, Kluyveromyces, Williopsis, Pichia, Debaromyces, and Zygosaccharomyces [164]. The anti-bacterial capability of S. cerevisiae is attributed to: a) Secretion of inhibitory proteins b) Production of extracellular protease c) Stimulation of immunoglobulin A d) Procurement and eradication of secreted toxins e) Killer toxins, sulfur dioxide, etc. Sequential re-pitching of Saccharomyces biomass is a common process during brewing. Therefore, yeast is reused many times before its final dumping [165]. Hence, yeast develops an adaptive response against oxidative stress like that of human cells, leading to the accumulation of vitamins (B6 and B12) and minerals (enzyme co-factors including zinc, manganese, and copper) in the yeast cell. Phenolic compounds are also adsorbed by Saccharomyces from the exterior medium, which increases the phenolic content and antioxidant activity within yeast cells [166]. Efficient means are required to disrupt yeast cell walls and separate the products of interest, which are further used for food applications. However, increasing consumers' fears regarding the toxicity of killer yeast strains present in food, and milk products, constituting a direct risk to public health.

Microalgae
The antimicrobial activity of microalgae is due to the presence of phytochemicals, including indoles, acetogenins, terpenes, fatty acids, phenols, and volatile halogenated hydrocarbons (Table 7) [167]. Moreno et al. [168] reported that Chaetoceros muelleri extracts' antimicrobial activity is due to their lipid configuration, whereas Dunaliella salina is attributed to the presence of β-cyclocitral, α and β-ionone, phytol, and neophytadiene. In natural environmental conditions, microalgal cells release fatty acids against predators and pathogenic bacteria. It is elucidated that these fatty acids act on bacterial cell membranes causing cell seepage, a decline in nutrient intake, and reduced cellular respiration, ultimately resulting in cell death [169]. Chlorellin, the first antibacterial compound from a microalga Chlorella is composed of a mixture of fatty acid was isolated by Pratt et al. [177] reported to inhibit the activity of both Gram-positive and Gram-negative bacteria. Arthrospira platensis, commercially known as Spirulina had MIC of 0.20% for L. innocua and P. fluorescens and 0.25% for Serratia, whereas minimal bactericidal concentration (MBC) value was 0.30% for all these species [178]. HPTLC screening and GC-MS analyses were done to detect and screen the macroalgae's antimicrobial compounds. Peptides namely AQ-1756, AQ-1757, and AQ-1766 identified from Tetraselmis suecica exhibited an antibacterial activity resulting in decreasing cell viability (human embryonic kidney cells) (HEK293) up to 75% after 24 h of treatment. AQ-1766 was more active against Gram-positive than Gram-negative bacteria, with MBC values between 40 and 50 µM [179]. Mendiola et al. [180] demonstrated that lipid fractions obtained from Chaetoceros muelleri by the supercritical CO2 method have antibacterial activity against Staphyloccocus aureus and E. coli. In contrast, extraction via classic methods using hexane, dichloromethane, and methanol solvent did not possess any activity against E. coli. However, these studies were unable to elaborate on these bioactive compounds' antibacterial activity's exact mode of action.
Axenic microalgae co-culture can produce compounds with potent activity against pathogenic bacteria. Kokou et al. [181] reported that axenic cultures of Tetraselmis chui, Chlorella minutissima, Isochrysis sp. and Nannochloropsis sp. inhibit Vibrio harveyi . The potent activity of microalgal compounds against microbes requires further development in the search for drugs and food preservatives. Therefore, the exploitation in medicine deserves to be further investigated.

Discussion and Future prospect
One of the major challenges healthcare services face worldwide is the excessive use of antibiotics as medicine and in food production leading to microbiome disruption. With the burst of antimicrobial resistance strains, there is a continuous decline in the antimicrobial drug pipeline, and it has become mandatory to discover and develop new agents/metabolites to tackle antibiotic resistance. The microbial metabolites were used as antibiotics with the discovery of penicillin and are easy to isolate, culture, and engineered compared to plants. After discovering penicillin, many drug discoveries from microbial sources had been reported, and the advancement of techniques such as genetic engineering during the 1970s, which later on opened the door to the ignored source, i.e., microbial metabolites [182].
Microbial products are vital constituents of new drug molecules, and ample research is being carried out to search for novel antimicrobial agents from biological sources that include bacteria, actinomycetes, fungi, yeast, etc. LAB producing bacteriocins, antimicrobial ribosomal peptides, is a promising advancement for the food and feed industry by extending their shelf life and safeguarding consumers' health. Actinomycetes, particularly Streptomyces, exhibited effective antagonistic activity and played a significant role in drug discovery and development. The bioactive compounds obtained so far from actinomycetes include streptomycin, antimycin, vinaceuline, bafilomycin, diastaphenazine, etc. However, not all of them have achieved commercial success. This might be due to the low potency of drugs, their pharmacological properties, related safety issues, or the rapid advent of resistant strains.
In the ongoing search for novel antibiotics, archaeocins have generally been overlooked. Halocins are extensively reviewed and halocin H6 has been revealed to inhibit the Na+/H+ antiporter causing cell lysis and death of pathogens. Further studies on purifications and characterizations to the archaeocins and sulfolobicins are in progress, resulting in the economical production of bioactive compounds for pharmaceutical applications. It becomes desirable to expand our understanding of the effectiveness and use of other naturally occurring ribosomally-synthesized peptide antimicrobials to understand their implantation and survival strategies and quantitatively estimate their efficacy for future applications pharmaceutical and health care sectors.
Many achievements have been made regarding fungal antibiotics starting from penicillin. Fungi synthesized small quantities of bioactive compounds in response to explicit environmental conditions, which cannot be reproduced easily in the laboratory. Therefore, effective methods of strain improvement are required to increase the ability of a fungus to produce bioactive metabolites in large amounts consistently. Also, to develop novel antimicrobial drugs from these fungal metabolites, commercial-scale synthesis must be accomplished, potentially through strain improvement, optimizing growth conditions, and incorporating techniques, such as metabolomics, genomics, and pathway engineering.
Endophytic and marine-derived fungi offer a suitable substitute against toxic, ineffective, and expensive antimicrobial drugs because they act as a warehouse filled with novel bioactive compounds with never-ending potentials for biological properties. Apart from other fungal species, mushrooms are continued to be consumed in their natural forms since time immemorial.
Antimicrobials, isolated from mushrooms, are important as potential substitutes to synthetic drugs and preservatives, whose protection and influence on the health of humans, animals, and food are still uncertain. This review demonstrates that edible mushrooms are a potent source of countless bioactive substances with antimicrobial activity. Hence, they must not be considered only as a culinary delicacy but also taken as therapeutic agents. However, we are still required to develop methods for isolation, purification, identification, and characterization of antimicrobial compounds to develop antibiotics.
Microalgae are a promising source of high-value products, and large-scale screening programs have been conducted to discover the antimicrobial potential of microalgal extracts against pathogenic and foodborne organisms. However, major antibacterial and antifungal activity reports were predominantly from the chlorella sp. and Chlamydomonas sp. Still, many hurdles exist in developing the marine product, including resource supply issues, large-scale production, production cost, determination of the efficacy target [183]. These obstacles must be bypassed by optimizing mass culturing conditions, utilizing biotechnological techniques, etc. Along with these measures, extensive clinical trials will be needed to determine the in-vivo fortune of antimicrobials from microbial extracts on mammalian cells. A consolidated bio-refinery approach must be accepted to expand the utility of microalgae biomass [167]. Systematic research should be carried to evaluate the microalgae potential as a promising biotechnology tool.
Although killer yeasts strain secret toxins, many yeasts have antimicrobial activities inhibiting other yeast strains, molds, and bacteria. Regardless of this, preliminary research has been conducted on the bioactive compounds from S. cerevisiae; the widely studied yeast has been involved in many biotechnological processes because of its good fermentation capacity, probiotics, and health benefits. Therefore, developing and using robust screening and high-throughput methods will be essential to study yeast antimicrobial activity, thereby increasing the chances of discovering and identifying novel antibiotic molecules. To achieve this goal, the experimental design must include all possible variables, including recovering both intra-and extracellular extracts produced by microbes under variable growth conditions, utilizing potential inducers of antimicrobial activity, and testing these compounds against a more significant number of targets.
The detailed functional and structural knowledge would explain the mode of action and performance at cellular and molecular levels.

Conclusions
In the present review, it could be concluded that the promising novelty of microorganisms brought them under the focus of intensive research. Microbes' applications in human foods, animal feeds, agriculture, and increased market demand are motivating to continue the research and development of novel antibiotics and preservatives. Furthermore, the molecular docking and structural analysis approach can better design pathogenspecific antimicrobial agents that exhibit lesser toxicity, higher selectivity, and biodegradability. Therefore, exploiting microbial biodiversity and biotechnological potential to determine new pipelines for bioactive compounds discovery is approached to treat lifethreatening diseases and safeguard human health.