Antimicrobial agents play a significant role in the treatment of infectious diseases caused by pathogenic microorganisms with various modes of action. Since the fortuitous discovery of penicillin in 1928, hundreds of antibiotics have been approved for clinical use. However, some of these drugs have become less efficacy or unavailability simultaneously owing to the development of antimicrobial resistance (AMR), in which a pathogenic microbe evolves a survival mechanism that protects the drug target by modification or replacement, or degradation or modification of the antibiotic to render it harmless, such as MRSA (methicillin-resistant Staphylococcus aureus), multidrug-resistant S. aureus (MDRS), VREF (vancomycin-resistant Enterococcus faecium), CRKP (cephalosporin-resistant Klebsiella pneumoniae) [1]. Antimicrobial resistance has become an increasing threat to human health and is widely considered to be the next global pandemic [2]. Therefore, it is an urgent need for the discovery of new antimicrobial drugs with novel structural scaffolds and new modes of action.

2. Antibacterial Secondary Metabolites

Bacterial infection is a common clinical disease that can affect a variety of organs and tissues. Fusarium-derived antibacterial SMs have a wide array of structural motifs, most of which are polyketides, followed by alkaloids, terpenoids, and cyclopeptides. According to antibacterial properties, these chemicals are divided into three groups, including anti-Gram-positive bacterial SMs (1–50, Figure 1), anti-Gram-negative bacterial SMs (51–64, Figure 2) and both anti-Gram-positive and anti-Gram-negative bacterial SMs (65–81, Figure 3).

2.1. Anti-Gram-Positive Bacterial SMs

Fifty Fusarium-derived SMs (1–50, Figure 1) had been characterized and displayed various bactericidal effects on Gram-positive strains, such as Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, multidrug-resistant S. aureus, Mycobacterium tuberculosis, Bacillus subtilis, etc. Fusariumins C (1) and D (2) are two new polyketides produced by an endophytic strain F. oxysporum ZZP-R1 from coastal plant Rumex midair Makino displayed medium effect on S. aureus with MIC (minimum inhibitory concentration) values of 6.25 and 25.0 μM, respectively ^[3][4]. Two triterpene sulfates (3 and 4) isolated from F. compactum exhibited weak activity toward S. aureus and Streptococcus strains in the range of 6–50 µg/mL ^[4][5]. Enniatins (5–10), a group of antibiotics commonly synthesized by various Fusarium strains, are six-membered cyclic depsipeptides formed by the union of three molecules of D-α-hydroxyisovaleric acid and three N-methyl-L-amino acids ^[5][6]. Three enniatins (8–10), beauvericin A (11) and trichosetin (12) were obtained from an endophytic fungus, Fusarium sp. TP-G1 and showed moderate anti-S. aureus and anti-methicillin-resistant S. aureus effects with MIC values in the range of 2–16 µg/mL ^[6][7]. Two enantiomers (12 and 13) were separated from the culture broth of F. oxysporum FKI-4553 and found to have an inhibitory effect on the undecaprenyl pyrophosphate synthase activity of S. aureus with IC₅₀ values of 83 and 30 µM, respectively ^[7][8]. Lateritin (14) derived from Fusarium sp. 2TnP1–2 showed anti-S. aureus activity at 2 µg per disc with 7 mm of inhibition zone ^[8][9]. A new polycyclic quinazoline alkaloid (15) displayed moderate antibacterial activity against methicillin-resistant S. aureus and multidrug-resistant S. aureus, with the same MIC value of 6.25 µg/mL ^[9][10]. Three pyranopyranones (16–18) showed weak inhibitory activities against S. aureus, methicillin-resistant S. aureus, and multidrug-resistant S. aureus ^[10][11]. Compound 19 was a new pyran-2-one with weak activity against methicillin-resistant S. aureus and was shown to be the inhibitor of the quorum-sensing mechanism of S. aureus and Pseudomonas aeruginosa ^[11][12]. Trans-dihydrofusarubin (20) and seven analogs (21–27) had significant antibiotic activity against S. aureus (MIC values < 4 µg/mL), and compounds 26 and 27 exhibited potent activity against S. pyogenes ^[12][13]. Five naphthoquinones 28–32 showed anti-Mycobacterium tuberculosis activity with MICs ranging from 25 to 50 µg/mL ^[13][14]. Compounds 32 and 33 displayed moderate antibacterial activity against S. aureus and potent activities against B. cereus and S. pyogenes with MIC values of <1 µg/mL as compared to ciprofloxacin, whose MIC value was 0.15 and 10 µg/mL, respectively ^[14][15]. Linoleic acid (34) and epi-equisetin (35) had certain inhibitory activity against S. aureus and multidrug-resistant S. aureus ^[15][16]. (−)-4,6′-anhydrooxysporidinone (36) was obtained from F. oxysporum and showed weak anti-multidrug-resistant S. aureus and moderate anti-B. subtilis effects ^[16][17]. Fusaroxazin (37), a novel antimicrobial xanthone derivative from F. oxysporum, possessed significant antibacterial activity towards S. aureus and B. cereus, with MIC values of 5.3 and 3.7 µg/mL, respectively ^[17][18]. Neomangicol B (38) isolated from the mycelial extract of a marine Fusarium strain was found to inhibit B. subtilis growth with a potency similar to that of the antibiotic gentamycin ^[18][19]. Three aromatic polyketides (39–41) were produced by strain F. proliferatum ZS07 and possessed potent antibacterial activity against B. subtilis with the same MIC values of 6.25 µg/mL ^[19][20]. Two sesterterpenes (42 and 43) produced by F. avenaceum SF-1502 displayed stronger antibacterial activity against B. megaterium than positive controls (ampicillin, erythromycin, and streptomycin) ^[20][21]. 4,5-Dihydroascochlorin (44) had strong antibacterial activity towards Bacillus megaterium ^[21][22]. Fusariumnols A (45) and B (46) were two novel anti-S. epidermidis aliphatic unsaturated alcohols isolated from F. proliferatum 13,294 ^[22][23]. Fungerin (47) displayed weak antibacterial activity against S. aureus and S. pneumoniae ^[23][24]. Compounds 48–50 were purified from F. oxysporum YP9B and showed a potent inhibitory effect on S. aureus, E.faecalis, S. mutans, B. cereus, and M. smegmatis with MICs of less than 4.5 µg/mL ^[24][25].

2.2. Anti-Gram-Negative Bacterial SMs

Butenolide (51) was a fusarium mycotoxin from unknown origin strain Fusaium sp. and showed selective inhibitory activity against E. coli ^[25][26]. Extensive chemical investigation of the endophytic fungus F. solani JK10 afforded nine 2-pyrrolidone derivatives (52–60), which displayed antibacterial activity against E. coli with MIC values of 5–10 µg/mL. Particularly, three lucilactaene analogs (52–54) had strong inhibitory effects on Acinetobacter sp., comparable to the positive control streptomycin ^[26][27]. One new aromatic polyketide, karimunones B (61), together with compounds 62 and 63, was obtained from sponge-associated Fusarium sp. KJMT.FP.4.3 and exhibited anti-multidrug resistant Salmonella enterica ser. Typhi activity with a MIC of 125 µg/mL ^[27][28]. Fusapyridon A (64) is produced by an endophytic strain, Fusarium sp. YG-45 demonstrated moderate antibacterial activity against Pseudomonas aeruginosa with a MIC value of 6.25 µg/mL ^[28][29].

2.3. Both Anti-Gram-Positive and Anti-Gram-Negative Bacterial SMs

Seventeen Fusarium-derived SMs (65–81, Figure 3) were shown to have both anti-Gram-positive and anti-Gram-negative activity. Seven naphthoquinones (65–71) demonstrated moderate activities against an array of Gram-positive and Gram-negative bacteria, such as B. megaterium, B. subtilis, C. perfringens, E. coli, methicillin-resistant S. aureus, P. aeruginosa, S. aureus, and S. pyogenes ^{[12][20][29][30]}[13,21,30,31]. The mechanism of action (MoA) study indicated that compounds 66 and 71 could stimulate the oxygen consumption of bacterial cells and induce cyanide-insensitive oxygen consumption, which results in the generation of superoxide anion and hydrogen peroxide ^[31][32]. Compounds 72–75 were polycyclic terpenoids, respectively, produced by three Fusarium strains ^[32][33][34][33,34,35]. Compound 72 had significant activity against S. aureus and P. aeruginosa with a MIC value of 6.3 µg/mL, and 73 showed moderate activities against Salmonella enteritidis and Micrococcus luteus with MIC values of 6.3 and 25.2 µg/mL, respectively, while 74 showed a broad spectrum of antibacterial activity and 75 exhibited moderate antibacterial activities against S. aureus and E. coli with the same MIC value of 16 µg/mL. Two xanthine oxidase inhibitory cerebrosides (76 and 77) were identified and purified from the culture broth of Fusarium sp. IFB-121 and showed strong antibacterial activities against B. subtilis, E. coli, and P. fluorescens with MICs of less than 7.8 µg/mL ^[35][36]. Enniatins J₁ (78) and J₃ (79) were two hexadepsipeptides with an array of antibacterial activity toward C. perfringens, E. faecium, E. coli, S. dysenteriae, S. aureus, Y. enterocolitica, and lactic acid bacteria except for B. adolescentis ^[36][37]. Halymecin A (80) was produced by a marine-derived Fusarium sp. FE-71-1 and exhibited a moderate inhibitory effect on E. faecium, K. pneumoniae, and P. vulgaris with the MIC value of 10 µg/mL ^[37][38]. Fusaequisin A (81) was isolated from rice cultures of F. equiseti SF-3-17 and found to have moderate antimicrobial activity against S. aureus NBRC 13,276 and P. aeruginosa ATCC 15,442 ^[38][39].

3. Antifungal Secondary Metabolites

Invasive fungal infections are very common in immunocompromised patients (such as acquired immune deficiency syndrome and organ transplantation) and have become a global problem resulting in 1.7 million deaths every year ^[39][40][41][40,41,42]. Furthermore, the overuse of antifungal agents increases opportunistic pathogen resistance, which had been listed as one of the dominant threats by the World Health Organization in 2019. Therefore, the urgent need for new antimycotics with novel targets is undeniable. Till the end of 2022, twenty-seven antifungal SMs (82–108, Figure 4) had been discovered from Fusarium strains. Compounds 82–84 are three anti-C. albicans glycosides belong to the papulacandin class ^[42][43][43,44]. The MoA study suggested that compound 82 is an inhibitor of glutamine synthetase (GS) enzyme for (l,3)-β-glucan biosynthesis ^[42][43]. CR377 (85) was a new α-furanone derivative from an endophytic Fusarium sp. CR377 and showed a similar antifungal effect on C. albicans with nystatin ^[44][45]. Compounds 86 and 87 were two zearalenone analogs and exhibited weak activity against Cryptococcus neoformans ^[45][46]. Neofusapyrone (88) produced by a marine-derived Fusarium sp. FH-146 displayed moderate activity against A. clavatus F318a with a MIC value of 6.25 µg/mL ^[46][47]. Six cyclic depsipeptides 89–94 had been isolated from several Fusarium strains and found to have significant inhibitory activities against pathogenic fungi, such as C. albicans ^[47][48], C. glabrata, C. krusei, V. ceratosperma, and A. fumigates ^[48][49]. Cyclosporin A (91) has long been recognized as an immunosuppressant agent and could inhibit the growth of sensitive fungi after their germination ^[49][50][50,51]. Parnafungins A-D (95–98) were isoxazolidinone-containing natural products and demonstrated broad-spectrum antifungal activity with no observed activity against bacteria. The targeted pathway of these alkaloids was determined to be the mRNA 3`-cleavage and polyadenylation process ^[51][52][52,53]. One N-hydroxypyridine derivative (99) showed antifungal activity against C. albicans and Penicillium chrysogenum with MICs of 16 and 8 µg/mL, respectively ^[53][54]. Indole acetic acid (100) exhibited activity against the fluconazole-resistant C. albicans (MIC = 125 µg/mL) ^[54][55]. Fusaribenzamide A (101) possessed a significant anti-C. albicans activity with MIC of 11.9 µg/disc compared to nystatin (MIC = 4.9 µg/disc) ^[55][56]. Three pyridone derivatives (102–104) displayed significant activities against multidrug-sensitive S. cerevisiae 12geneΔ0HSR-iERG6, and the MoA study indicated that these substances have a potent inhibitory effect on NADH-cytochrome C oxidoreductase ^[56][57]. Compounds 105–107 were derived from strain F. oxysporum N17B, and the former (105 and 106) showed selective fungistatic activity against Aspergillus fumigatus, and the latter (107) had selective potent activity against C. albicans through inhibition of phosphatidylinositol 3-kinase ^[57][58]. Culmorin (108) displayed remarkable antifungal activity against both marine (S. marina, M. pelagica) and medically relevant fungi (A. fumigatus, A. niger, C. albicans, T. mentagrophytes) ^[58][59][59,60].

4. Both Antibacterial and Antifungal Secondary Metabolites

Till the end of 2022, forty-one SMs (109–149, Figure 5) with both antibacterial and antifungal effects had been discovered from Fusarium spp. Among these Fusarium-derived 1,4-naphthoquinone analogs (109–115), compound 109 showed potent anti-Gram-positive bacteria activity against B. cereus and S. pyogenes with MIC of <1 µg/mL and anti-C. albicans activity with IC₅₀ (the half maximal inhibitory concentration) of 6.16 µg/mL ^[13][14], and 110–115 demonstrated moderate inhibitory effects on S. aureus, C. albicans, and B. subtilis ^[60][61]. Bikaverin (116) was found to have anti-E. coli and antifungal (P. notatum, Alternaria humicola, and A. flavus) activity ^[47][61][62][48,62,63]. Lateropyrone (117) was the same SM as F. acuminatum, F. lateritium, and F. tricinctum and displayed good antibacterial activity against B. subtilis, S. aureus, S. pneumoniae, methicillin-resistant S. aureus, Mycobacterium tuberculosis, and vancomycin-resistant of E. faecalis and significant inhibitory activity towards the growth of C. albicans ^{[63][64][65][66]}[64,65,66,67]. BE-29,602 (118) was a novel antibiotic of the papulacandin family, showing good activity against C. albicans, S. cerevisiae, S. pombe with MIC values < 1 µg/mL and moderate activity against B. subtilis and P. chrysogenum with the MIC values < 8 µg/mL ^[43][67][44,68]. Fusarielin A (119) was a meroterpenoid with moderate antifungal activities against A. fumigatus and F. nivale and weak antibacterial effect on S. aureus, methicillin-resistant S. aureus, and multidrug-resistant S. aureus ^[10][68][11,69]. Three helvolic acid derivatives (120–122) displayed potent antifungal and antibacterial activities against B. subtilis, S. aureus, E. coli, B. cinerea, F. Graminearum, and P. capsica ^[69][70]. Fusartricin (123) had moderate antimicrobial activity against E. aerogenes, M. tetragenu, and C. albicans with the same MIC value of 19 µM ^[33][34]. Compounds 124–128 are pyrone family members and showed antimicrobial activity against bacteria (such as B. subtilis, S. aureus, Vibrio parahaemolyticus, C. kefyr, and P. aeruginosa) and fungi (such as A. clavatus, Geotrichum candidum, C. albicans, M. albican, and S. cerevisiae) ^{[46][70][71][72][73]}[47,71,72,73,74]. Fusaric acid (129), one of the most significant mycotoxins from Fusarium strains, displayed a broad spectrum of moderate antimicrobial activity against Bacillus species, Acinetobacter baumannii, Phytophthora infestans, etc. ^[74][75][76][75,76,77]. Equisetin (130) was shown to be active against several strains of Gram-positive bacteria (B. subtilis, Mycobacterium phlei, S. aureus, methicillin-resistant S. aureus, and S. erythraea) and the Gram-negative bacteria Neisseria perflava at concentrations of 0.5–4.0 µg/mL, as well as antifungal activity toward P. syringae and R. cerealis ^[77][78][78,79]. Fusarithioamides A (131) and B (132) demonstrated antibacterial potential towards B. cereus, S. aureus, and E. coli compared to ciprofloxacin and selective antifungal activity towards C. albicans compared to clotrimazole ^[79][80][80,81]. Beauvericin (133) and enniatins A, A1, B and B1 (134–137) are cyclic hexadepsipeptides with a wide array of highly antimicrobial activities against bacteria (such as B. subtilis, S. aureus, methicillin-resistant S. aureus, etc.) and fungi (such as C. albicans, B. bassiana, T. harzianum, etc.) ^{[81][82][83][84][85]}[82,83,84,85,86]. Unlike most antibiotics, cell organelles or enzyme systems are the targets of the antibiotic 133 ^[86][87]. As a drug efflux pump modulator, furthermore, compound 133 had the capability to reverse the multi-drug resistant phenotype of C. albicans by blocking the ATP-binding cassette transporters and to repress the expression of many filament-specific genes, including the transcription factor BRG1, global regulator TORC1 kinase ^[87][88]. Fusaramin (138) displayed anti-Gram-positive and anti-Gram-negative bacterial activity and could inhibit the growth of S. cerevisiae 12geneΔ0HSR-iERG6 ^[56][57]. Compounds 139–142 were isolated from F. oxysporum YP9B and exhibited a significant antimicrobial effect against bacterial and fungi at concentrations of 0.8–6.3 µg/mL ^[24][25]. Seven SMs (143–149) were separated from an endophytic fungus F. equiseti, and showed antibacterial (such as B. subtilis, S. aureus, B. megaterium) and anti-C. albicans activities ^[88][89].

5. Antiviral Secondary Metabolites

The infections by viruses in humans resulted in millions of deaths globally and are accountable for viral diseases, including HIV/AIDS, hepatitis, influenza, herpes simplex, common cold, etc. ^[89][90]. The emergence of new viruses like Ebola and coronaviruses (SARS-CoV, SARS-CoV-2) emphasizes the need for more innovative strategies to develop better antiviral drugs. Twenty-three Fusarium-derived SMs (64, 99, 105, 135–137, 140–142, 144–147, 149–158, Figure 6) had been shown to have antiviral effects. The isolation of fusaricide (99) was guided by the Rev (regulation of virion expression) binding assay ^[53][54]. Fusapyridon A (64) and oxysporidinone (105) displayed antiviral activity against the coronavirus (HCoV-OC43) with IC₅₀ values of 13.33 and 6.65 μM, respectively ^[90][91]. Their enniatins (135–137) were found to protect human lymphoblastoid cells from HIV-1 infection with an in vitro “therapeutic index” of approximately 200 (IC₅₀ = 1.9, EC₅₀ = 0.01 µg/ mL, respectively) ^[91][92]. The antiviral activity against HSV type-1 was determined to be 0.312 µM for compound 140 and 1.25 µM for 141 and 142 ^[24][25]. Three indole alkaloids (150–152) were obtained from a marine-derived Fusarium sp. L1 and exhibited inhibitory activity against the Zika virus (ZIKV) with EC₅₀ values of 7.5, 4.2, and 5.0 μM, respectively ^[92][93]. A chemical study of an endophytic fungus F. equiseti led to the isolation of compounds 144–147 and 153–157, of which 149 and 157 showed good potency against hepatitis C virus NS3/4A protease, while 144 and 155 were the most potent hepatitis C virus NS3/4A protease inhibitors ^[88][89]. Coculnol (158) was a penicillic acid from a coculture of F. solani FKI-6853 and Talaromyces sp. FKA-65 displayed an inhibitory effect on A/PR/8/34 (H1N1) with an IC₅₀ value of 283 µg/mL ^[93][94].

6. Antiparasitic Secondary Metabolites

Parasitic diseases caused by protozoa, helminths and ectoparasites affect millions of people each year and result in substantial morbidity and mortality, particularly in tropical regions ^[94][95]. Therefore, new antiparasitic agents are urgently needed to treat and control these diseases. A total of 39 antiparasitic SMs (23, 28, 29, 59, 108, 93, 116, 133–137, 159–185, Figure 7) had been isolated and characterized from Fusarium strains. Five naphthoquinones (23, 29, 30, 109, and 159) and one anthraquinone (160) showed weak inhibitory activity toward the most deadly malaria parasite Plasmodium falciparum K1 with IC₅₀ values in the range 9.8–26.1 µM ^[95][96]. However, compound 93 displayed significant antiplasmodial activity toward P. falciparum (D6 clone) with an IC₅₀ value of 0.34 µM ^[48][49]. Bikaverin (116) was specifically effective against Leishmania brasiliensis, which is one of the main causes of cutaneous leishmaniasis in the Americas ^[96][97]. Beauvericin (133) was reported to inhibit Trypanosoma cruzi with an IC₅₀ value of 2.43 μM and L. braziliensis with an EC₅₀ value of 1.86 μM ^[97][98][98,99]. In addition to antibacterial and antifungal effects, enniatins (134–137) exhibited mild anti-leishmanial activity by inhibition of the activity of thioredoxin reductase enzyme of P. falciparum ^[5][6]. Integracides F, G, H, and J (161–164) were also shown to have stronger anti-leishmanial activity towards L. donovani than the positive control pentamidine (IC₅₀ = 6.35 µM) ^[99][100]. Among twelve lucilactaene derivatives (165–176), compounds 166–168 showed very potent antimalarial activity toward P. falciparum (IC₅₀ = 0.0015, 0.15, and 0.68 μM, respectively) ^{[100][101][102]}[101,102,103]. Structure−activity relationship study suggested that epoxide is extremely detrimental, and demethylation of the lucilactaene methyl ester and formation of the free carboxylic acid group resulted in a 300-fold decrease in activity. Nine cyclic tetrapeptides (177–185) are apicomplexan histone deacetylase (HDA) inhibitors ^{[103][104][105]}[104,105,106]. Particularly, compound 177 was an excellent inhibitory agent (IC₅₀ < 2 nM) and showed in vivo high efficacy against P. berghei malaria in mice at less than 10 mg/kg.