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    Topic review

    Antimicrobial Compounds from Endolichenic Fungi

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    Definition

    A lichen is a symbiotic relationship between a fungus and a photosynthetic organism, which is algae or cyanobacteria. Endolichenic fungi are a group of microfungi that resides asymptomatically within the thalli of lichens. Endolichenic fungi can be recognized as luxuriant metabolic artists that produce propitious bioactive secondary metabolites. 

    1. Introduction

    Thousands of microorganisms, including fungi and bacteria, often associate with living and dead plant tissues [1]. Oftentimes, the importance of these microorganisms is unobserved; only the saprotrophic and pathogenic relationships are being investigated, and are viewed as a troublesome group of organisms. However, there are groups of micro-organisms that are phyto-friendly and able to produce a plethora of secondary metabolites with significant biological activities that will aid them to adapt better to their surroundings [2][3].
    Lichens are an amalgamation or a symbiotic partnership between a fungus and a photosynthetic organism. The heterotrophic fungal partner is termed as a “mycobiont”, while the photoautotrophic “photobiont”, could be either green algae or cyanobacteria [4][5][6]. As the mycobiont usually plays the more prominent member, lichens have traditionally exhibited characteristics similar to theirs. The two partners share water, nutrients and gases [6] and this mutualism allows the lichens to develop under extremely exceptional ecological conditions like deserts, rocky coasts, alpine zones and droughts [5][6][7][8]. Living under these unusual conditions enables lichens to give birth to a variety of luxurious compounds with complex structures and numerous bioactivities, making this a highly interesting stream for natural product chemists to pursue [8][9][10]. However, lichen flora is less abundant in the neighbourhood of urban and industrialized areas, as lichens are easily affected by air pollutants [11]. Lichens display a wide distribution of more than 20,000 different species worldwide [12], and have been utilized on various occasions in the past, such as in food, perfumes, dyes and as antidotes for folk medication [10][11].

    2. Antimicrobial Compounds Extracted from Endolichenic Fungi

    The need for new antimicrobial drugs is enhanced by the emergence of microbial resistance against almost all the currently available antibiotics and the sudden appearance of deadly viral infections [13]. Discovery of novel antimicrobial drugs was speculated as a solution to the growing threat of antibiotic-resistant microorganisms by the former secretary general of the United Nations, Ban Ki-Moon, at the UN General Assembly in 2016 [14].
    The significant role of fungal species in producing antibiotics is elicited after the discovery of Penicillin G in 1928 [7]. Symbiotic fungal species like endophytic fungi are known to produce a plethora of antimicrobial compounds pertinent in therapeutics and agriculture [15]. Similar to other symbiotic fungi, ELF produces several secondary metabolites, which protect the lichen from biotic as well as abiotic stress [16]. ELF-derived antimicrobial compounds are one such group of metabolites essential to overcome the constant microbial threats faced by lichens. In some cases, extracts or natural products isolated from ELF show strong antimicrobial properties even though these bioactivities are not naturally observed within their ecological niche.
    The discovery of many antimicrobial metabolites from ELF, establishes a hopeful satisfaction to the perpetual thirst for new antimicrobial drugs. However, these compounds might need further optimizations to modify their pharmacological and toxicological profiles. On the other hand, the development of synthetic pathways to produce these compounds, an industrial scale is essential to minimize the cost of production and minimize the environmental impacts. Thus, a detailed summary is provided here to describe the antimicrobial compounds isolated from ELF, including their sources, structures, activities and potencies in antimicrobial drug discovery.
    Addressing the aforesaid requirement, Table 1 of this review provides an overview of antimicrobial secondary metabolites isolated from ELF, which includes 31 antibacterial compounds, 58 antifungal compounds, two antiviral compounds, and one antiplasmodial (antimalarial) compound. The structures of these compounds are given in the Figure 1. Most of the authors have either reported only the antimicrobial properties of the lichenic and endolichenic fungal extracts without isolation of the metabolites responsible for the relevant bioactivity or have not quantified it in the form of Minimum Inhibitory Concentration (MIC) or IC50. However, only the endolichenic fungal secondary metabolites, whose antimicrobial properties are satisfactorily quantified, are summarized in this review. For ease of comparison, all of the antimicrobial potencies are presented in µg/mL and activities of the positive control are also given wherever available.
    Figure 1. Structures of the antimicrobial compounds isolated from ELF.
    Table 1. Antimicrobial Compounds Isolated from ELF.

    Lichen

    Endolichenic Fungi

    No.

    Compound

    Microorganism

    Activity (µg/mL)

    Positive Control

    Activity (µg/mL)

    Reference

    Diorygma hieroglyphicum

    Talaromyces funiculosus

    1

    Funiculosone

    Escherichia coli

    IC50 = 25

    -

    -

    [17]

    Staphylococcus aureus

    IC50 = 58

    -

    -

    2

    Mangrovamide J

    Escherichia coli

    IC50 = 65

    -

    -

    Staphylococcus aureus

    IC50 = 104

    -

    -

    3

    Ravenilin

    Escherichia coli

    IC50 = 23

    -

    -

    Pseudomonas aeruginosa

    IC50 = 96

    -

    -

    Staphylococcus aureus

    IC50 = 25

    -

    -

    Everniastrum sp.

    Ulocladium sp.

    4

    6-hydroxy-8-methoxy-3a-methyl-3a,9b-dihydro-3H-furo[3,2-c]isochromene-2,5-dione

    Bacillus subtilis

    IC50 = 25.0

    Gentamicin

    IC50 < 0.048

    [18]

    5

    6-O-methylnorlichexanthone

    Bacillus subtilis

    IC50 = 0.39

    6

    Altenusin

    Bacillus subtilis

    IC50 = 11.3

    7

    Alterlactone

    Bacillus subtilis

    IC50 = 11.8

    8

    Griseoxanthone C

    Bacillus subtilis

    IC50 = 0.35

    9

    Isoaltenuene

    Bacillus subtilis

    IC50 = 14.7

    10

    Norlichexanthone

    Bacillus subtilis

    IC50 = 0.58

    Methicillin Resistant Staphylococcus aureus.

    IC50 = 5.4

    Vancomycin

    IC50 < 1.03

    11

    Tricycloalternarene 1b

    Bacille Calmette-Guérin strain

    MIC = 125

    -

    -

    [19]

    Ulocladium sp. (CHMCC 5507)

    12

    Ophiobolin P

    Bacillus subtilis

    MIC = 12.6

    Gentamicin

    MIC = 0.05

    [20]

    Methicillin Resistant Staphylococcus aureus.

    MIC = 25.1

    Vancomycin

    MIC = 1.0

    13

    Ophiobolin T

    Bacille Calmette-Guérin strain

    MIC = 12.7

    Hygromycin

    MIC = 0.35

    Bacillus subtilis

    MIC = 6.3

    Gentamicin

    MIC = 0.05

    Methicillin Resistant Staphylococcus aureus

    MIC = 12.7

    Vancomycin

    MIC = 1.0

    Parmelinella wallichiana

    Nigrospora sphaerica

    14

    Alternariol

    Bacillus subtilis

    MIC = 31.2

    Amikacin sulfate

    MIC = 0.45

    [21]

    Escherichia coli

    MIC = 62.5

    MIC = 0.90

    Staphylococcus aureus

    MIC = 62.5

    MIC = 0.90

    15

    Alternariol-9-methyl ether

    Bacillus subtilis

    MIC = 62.5

    MIC = 0.45

    Pseudomonas

    fluorescens

    MIC = 31.2

    MIC = 0.90

    Staphylococcus aureus

    MIC = 62.5

    MIC = 0.90

    Parmotrema rampoddense

    Fusarium

    proliferatum

    16

    Acetyl tributyl citrate

    Klebsiella pneumoniae

    MIC = 125

    -

    -

    [22]

    Pseudomonas aeruginosa

    MIC = 125

    -

    -

    Staphylococcus aureus

    MIC = 125

    -

    -

    17

    Fusarubin

    Escherichia coli

    MIC = 1.56

    -

    -

    Pseudomonas aeruginosa

    MIC = 1.56

    -

    -

    Staphylococcus aureus

    MIC = 1.56

    -

    -

    Parmotrema ravum

    Aspergillus niger

    18

    Asperpyrone A

    Staphylococcus aureus MTCC 737

    IC50 = 112

    -

    -

    [23]

    19

    Aurasperone A

    Dickeya solani GBBC 1502

    IC50 = 63

    -

    -

    Listeria innocua LMG11387

    IC50 = 141

    -

    -

    Pectobacterium sp.

    IC50 = 76

    -

    -

    Pseudomonas aeruginosa MTCC 424

    IC50 = 160

    -

    -

    Pseudomonas syringae pv. Maculicola I11004

    IC50 = 80

    -

    -

    Staphylococcus aureus MTCC 737

    IC50 = 135

    -

    -

    20

    Carbonarone A

    Dickeya solani GBBC 1502

    IC50 = 88

    -

    -

    21

    Fonsecinone A

    Escherichia coli MTCC 443

    IC50 = 47

    -

    -

    Pseudomonas syringae pv. Maculicola I11004

    IC50 = 154

    -

    -

    Staphylococcus aureus MTCC 738

    IC50 = 120

    -

    -

    22

    Pyrophen

    Aeromonas hydrophila ATCC 7966

    IC50 = 78

    -

    -

    Listeria innocua LMG11387

    IC50 = 86

    -

    -

    Micrococcus luteus DPMB3

    IC50 = 63

    -

    -

    Sticta fuliginosa

    Xylariaceae sp. (CR1546C)

    23

    (R)-4,6,8-trihydroxy-3,4-dihydro-1(2H)-naphthalenone

    Bacillus subtilis

    IC50 = 104.2

    Streptomycin sulphate

    IC50 = 5.2

    [24]

    24

    18-O-acetylambuic acid

    Staphylococcus aureus ATCC 6538

    IC50 = 10.9

    Antimicrobial peptide (AMP)

     

    [25]

    25

    6,8-dihydroxy-(3R)-(2-oxopropyl)-3,4-dihydroisocoumarin

    Bacillus subtilis

    IC50 = 106.4

    Streptomycin sulphate

    IC50 = 5.2

    [24]

    26

    Ambuic acid

    Staphylococcus aureus ATCC 6538

    IC50 = 15.4

    Antimicrobial peptide (AMP)

     

    [25]

    Usnea sp.

    Hypoxylon fuscum

    27

    16-α-D-mannopyranosyloxyisopimar-7-en-19-oic acid

    Staphylococcus aureus CGMCC 1.2465

    MIC = 46.4

    Vancomycin Hydrochloride

    MIC = 3.12

    [26]

    28

    8-methoxy-1-naphthyl-β-glucopyranoside

    Staphylococcus aureus CGMCC 1.2465

    MIC = 30.1

    29

    Phomol

    Staphylococcus aureus CGMCC 1.2465

    MIC = 21.1

    -

    Coniochaeta sp.

    30

    Coniothienol A

    Enterococcus faecalis (CGMCC 1.2535)

    IC50 = 4.89

    Ampicillin

    IC50 = 2.61

    [27]

    Enterococcus faecium (CGMCC 1.2025)

    IC50 = 2.00

    IC50 = 0.51

    31

    Coniothiepinols A

    Enterococcus faecalis (CGMCC 1.2535)

    IC50 = 11.51

    IC50 = 2.61

    Enterococcus faecium (CGMCC 1.2025)

    IC50 = 3.93

    IC50 = 0.51

    Cetraria islandica

    Myxotrichum sp.

    32

    Myxodiol A

    Candida albicans SC 5314

    MIC = 128

    Fluconazole

    MIC = 2

    [28]

    Pestalotiopsis sp.

    33

    Ambuic acid derivative 1

    Fusarium oxysporum

    MIC = 8

    Ketoconazole

    MIC = 8

    [29]

    34

    Ambuic acid derivative 2

    Fusarium oxysporum

    MIC = 32

    MIC = 8

    35

    Ambuic acid derivative 4

    Verticillium dahlia

    MIC = 32

    MIC = 1

    36

    Ambuic acid derivative 5

    Fusarium gramineum

    MIC = 8

    MIC = 8

    Fusarium oxysporum

    MIC = 8

    MIC = 8

    Verticillium dahlia

    MIC = 16

    MIC = 1

    37

    Ambuic acid derivative 6

    Fusarium gramineum

    MIC = 8

    MIC = 8

    38

    Ambuic acid derivative 7

    Rhizoctonia solani

    MIC = 32

    MIC = 8

    39

    Ambuic acid derivative 8

    Rhizoctonia solani

    MIC = 32

    MIC = 8

    40

    Ambuic acid derivative 9

    Fusarium gramineum

    MIC = 32

    MIC = 8

    Fusarium oxysporum

    MIC = 16

    MIC = 8

    41

    Ambuic acid derivative 11

    Fusarium gramineum

    MIC = 32

    MIC = 8

    Cetrelia sp.

    Aspergillus sp. CPCC 400810

    42

    Isocoumarindole A

    Candida albicans

    MIC = 32.0

    Caspofungin

    MIC = 0.03

    [30]

    Diorygma hieroglyphicum

    Talaromyces funiculosus

    1

    Funiculosone

    Candida albicans

    IC50 = 35

    -

    -

    [17]

    Everniastrum sp.

    Ulocladium sp.

    43

    7-hydroxy-3-(2-hydroxy-propyl)-5-methyl-isochromen-1-one

    Candida albicans SC 5314

    IC50 = 45.4

    Amphotericin B

    IC50 = 1.03

    [18]

    44

    7-hydroxy-3,5-dimethyl-isochromen-1-one

    Candida albicans SC 5314

    IC50 = 18.7

    6

    Altenusin

    Aspergillus fumigatus

    IC50 = 57.5

    IC50 = 0.74

    8

    Griseoxanthone C

    Candida albicans SC 5314

    IC50 = 40.6

    IC50 = 1.03

    10

    Norlichexanthone

    Aspergillus fumigatus

    IC50 = 43.6

    IC50 = 0.74

    45

    Rubralactone

    Aspergillus fumigatus

    IC50 = 63.3

    IC50 = 0.74

    Candida albicans SC 5314

    IC50 = 54.7

    IC50 = 1.03

    Lethariella zahlbruckner

    Tolypocladium cylindrosporum

    46

    Pyridoxatin

    Candida albicans (Multiple strains)

    MIC =

    0.5 − 8.0

    Fluconazole

    MIC =

    1.0 − 2.0

    [31]

    Candida glabrata (Multiple strains)

    MIC =

    1.0 − 8.0

    MIC =

    1.0 − 2.0

    Candida krusei (Multiple strains)

    MIC =

    1.0 − 4.0

    MIC =

    1.0 − 2.0

    Candida tropicalis CT2

    MIC = 32

    MIC = 2.0

    Lobaria quercizans

    Aspergillus versicolor

    47

    3,7-dihydroxy-1,9-dimethyldibenzofuran

    Candida albicans

    MIC = 64

    Fluconazole

    MIC = 2

    [32]

    48

    Cordyol C

    Candida albicans

    MIC = 8

    49

    Diorcinol D

    Candida albicans

    MIC = 8

    50

    Diorcinol I

    Candida albicans

    MIC = 32

    51

    Violaceol I

    Candida albicans

    MIC = 8

    52

    Violaceol II

    Candida albicans

    MIC = 8

    Parmelia sp.

    Periconia sp.

    53

    3-(2-oxo-2H-pyran-6-yl)propanoic acid

    Aspergillus niger

    MIC = 31

    Cycloheximide

    MIC < 16

    [33]

    54

    Pericocin A

    Aspergillus niger

    MIC = 31

    Cycloheximide

    MIC < 16

    55

    Pericocin B

    Aspergillus niger

    MIC = 31

    56

    Pericocin C

    Aspergillus niger

    MIC = 31

    57

    Pericocin D

    Aspergillus niger

    MIC = 31

    58

    Pericoterpenoid A

    Aspergillus niger

    MIC = 31

    [34]

    Tolypocladium sp. (4259a)

    46

    Pyridoxatin

    Candida albicans

    MIC = 0.5

    -

    -

    [35]

    Parmelinella wallichiana

    Nigrospora sphaerica

    14

    Alternariol

    Candida albicans

    MIC = 80.0

    Ketoconazole

    MIC = 1.90

    [21]

    Parmotrema ravum

    Aspergillus niger

    59

    Aspergyllone

    Candida parapsilosis

    IC50 = 52

    -

    -

    [23]

    19

    Aurasperone A

    Candida krusei MTCC 9215

    IC50 = 373

    -

    -

    20

    Carbonarone A

    Candida albicans MTCC 227

    IC50 = 103

    -

    -

    Candida krusei MTCC 9215

    IC50 = 31

    -

    -

    22

    Pyrophen

    Candida albicans MTCC 227

    IC50 = 74

    -

    -

    Candida glabrata

    IC50 = 97

    -

    -

    Candida utilis IHEM 400

    IC50 = 62

    -

    -

    Pseudosyphellaria sp.

    Biatriospora sp.

    60

    2-acetonyl-3-methyl-5-hydroxy-7-methoxynaphthazarin

    Candida albicans

    MIC = 64

    Fluconazole

    MIC = 2

    [36]

    61

    6-deoxy-7-O-demethyl-3,4-anhydrofusarubin

    Candida albicans

    MIC = 32

    62

    Biatriosporin D

    Candida albicans

    MIC = 16

    63

    Biatriosporin K

    Candida albicans

    MIC = 64

    Sticta fuliginosa

    Xylariaceae sp. (CR1546C)

    64

    (3R,4S)-3,4,8-trihydroxy-3,4-dihydro-1(2H)-naphthalenone

    Candida albicans

    IC50 = 63.2

    Amphotericin B

    IC50 = 1.3

    [24]

    65

    (3S,4S)-3,4,6,8-tetrahydroxy-3,4-dihydro-1(2H)-naphthalenone

    Candida albicans

    IC50 = 67.8

    23

    (R)-4,6,8-trihydroxy-3,4-dihydro-1(2H)-naphthalenone

    Candida albicans

    IC50 = 78.2

    66

    2,4-dihydroxy-6-(2-oxopropyl)-benzoic acid

    Candida albicans

    IC50 = 101.3

    67

    5,6,8-trihydroxy-3(R)-methyl-3,4-dihydroisocoumarin

    Candida albicans

    IC50 = 71.4

    68

    6,8-dihydroxy-(3)-(2-oxopropyl)-isocoumarin

    Candida albicans

    IC50 = 98.1

    25

    6,8-dihydroxy-(3R)-(2-oxopropyl)-3,4-dihydroisocoumarin

    Candida albicans

    IC50 = 71.2

    69

    6,8-dihydroxy-3(R)-methyl-3,4-dihydroisocoumarin

    Candida albicans

    IC50 = 65.1

    70

    6,8-dihydroxy-3-[(2S)-2-hydroxypropyl]-isocoumarin

    Candida albicans

    IC50 = 99.1

    71

    6,8-dihydroxy-3-methylisocoumarin

    Candida albicans

    IC50 = 67.2

    Umbilicaria sp.

    Floricola striata

    72

    Floricolin A

    Candida albicans

    MIC = 16

    -

    -

    [37]

    73

    Floricolin B

    Candida albicans

    MIC = 8

    -

    -

    74

    Floricolin C

    Candida albicans

    MIC = 8

    -

    -

    75

    Floricolin D

    Candida albicans

    MIC = 64

    -

    -

    76

    Terphenyl 2

    Candida albicans

    MIC = 64

    -

    -

    Usnea baileyi

    Xylaria venustula

    77

    N-dodecyldiethanolamine (DDE)

    Candida albicans NCTC713

    MIC = 5.5

    -

    -

    [38][39]

    78

    Piliformic acid

    Colletotrichum gloeosporioides

    MIC = 625.2

    Captan

    MIC = 5000

    [38][40]

    Difenoconazole

    MIC = 8.1

    -

    Coniochaeta sp.

    31

    Coniothiepinols A

    Fusarium oxysporum (CGMCC 3.2830)

    IC50 = 13.12

    Carbendazim

    IC50 = 0.44

    [27]

    Parmelinella wallichiana

    Nigrospora sphaerica

    14

    Alternariol

    Herpes Simplex Virus

    IC50 = 34.9

    -

    -

    [41]

    15

    Alternariol-9-methyl ether

    Herpes Simplex Virus

    IC50 = 64.0

    -

    -

    Usnea baileyi

    Xylaria venustula

    79

    Isoplysin A

    Plasmodium falciparum

    MIC = 0.97

    -

    -

    [38][42]

    3. Structural Features Which Affect the Antimicrobial Activity of the Compounds

    ELF are metabolically versatile organisms that can produce secondary metabolites belonging to different natural product classes. However, by observing the structures of the compounds isolated from ELF categorized above, some common scaffolds leading to distinct antimicrobial properties can be identified. Knowledge of the bioactivities of such chemical scaffolds plays an important role in rational drug discovery and in natural product-related research to make intelligent guesses about the potentials of isolated compounds. The presence of a large pool of data about the potencies of natural compounds or their synthetic or semi-synthetic derivatives with common scaffolds will be helpful in structure–activity relationship (SAR) studies. In order to facilitate such studies, we have summarized the structural scaffolds in Table 2 that can be identified commonly among the antimicrobial compounds isolated from ELF.
    Table 2. Common structural scaffolds among the antimicrobial compounds isolated from ELF.

    Scaffold

    Compounds

    Molecules 26 03901 i001

    4, 9, 14, 15, 25, 42, 43, 44, 45, 53, 54, 56, 57, 66, 67, 68, 69, 70, 71

    Molecules 26 03901 i002

    1, 2, 3, 5, 8, 10, 18, 19, 20, 21, 30, 31, 55, 59

    Molecules 26 03901 i003

    24, 26, 33, 34, 35, 36, 37, 38, 39, 40, 41

    Molecules 26 03901 i004

    48, 49, 50, 51, 52

    Molecules 26 03901 i005

    17, 61, 63

    Molecules 26 03901 i006

    23, 64, 65

    The entry is from 10.3390/molecules26133901

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