Antibacterial and Antifungal Sesquiterpenoids: Chemistry, Resource, and Activity

Infectious diseases caused by bacteria and fungi are threatening human health all over the world. It is an increasingly serious problem that the efficacies of some antibacterial and antifungal agents have been weakened by the drug resistance of some bacteria and fungi, which makes a great need for new antibiotics. Sesquiterpenoids, with abundant structural skeleton types and a wide range of bioactivities, are considered as good candidates to be antibacterial and antifungal agents. In the past decades, many sesquiterpenoids were isolated from plants and fungi that exhibited good antibacterial and antifungal activities. In this review, the names, source, structures, antibacterial and antifungal degrees, and mechanisms of sesquiterpenoids with antibacterial and antifungal activity from 2012 to 2022 are summarized, and the structure-activity relationship of these sesquiterpenoids against bacteria and fungi is also discussed.


Introduction
The infections caused by drug-resistant bacteria and drug-resistant fungi are increasing across the world, and the threat of untreatable infections has been looming since the 21st century [1]. About 4.95 million people died from diseases related to antibiotic-resistant bacteria in 2019, and 1.27 million deaths were directly caused by antibiotic-resistant bacteria, which indicated that drug-resistant infections killed more people than HIV/AIDS (864,000 deaths) or malaria (643,000 deaths) [2]. Fungi also led to life-threatening systemic infections, with a mortality of over 1.6 million, which is three times more than malaria, resulting in the widespread use of antifungal agents [3]. The efficacy of the limited systemic antifungal drugs was counteracted by fungal attributes and host-and drug-related factors. Furthermore, some fungal pathogens showed notable rates of antifungal resistance, including Candida, Aspergillus, Cryptococcus, and Pneumocystis [4]. Therefore, it is a challenge that antibiotic resistance is not easy to overcome, requiring the development of newer antibacterial and antifungal drugs [3].
Natural products, which have rich resources and great bioactivities, play an important role in the discovery of new drugs [5]. A total of 60% of the small molecule drugs marketed from 1981 to 2019 arose from natural products or synthetic molecules based on natural product pharmacophores [6]. Sesquiterpenoids are the most abundant natural products, with various activities and excellent prospects in drug development. For example, qinghaosu (artemisinin), a sesquiterpenoid lactone from Artemisia annua discovered by Tu Youyou, has already reached the market as an antimalarial drug [7,8]. Santonin, a sesquiterpenoid compound, has been marketed as an anthelmintic and used for a long time against ascaris

Bisabolanes
Laurecomposin A, laurecomposin B, preintricatol, helianthol B, and gossonorol (1-5, Figure 3) were isolated from the red alga Laurencia tristicha. The complete 1H and 13C NMR assignments of compound 1 were made by a combination of 1H, 13C, DEPT, 1He1H COSY, HSQC, HMBC, and ROESY experiments and the absolute configuration was established by the modified Mosher's method. It was confirmed that compound 1 had activity against Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) SC5314 with MIC values of 26.8 and 16 µg/mL, respectively. Compound 1 also had an obvious inhibitory effect on Microsporum gypseum (M. gypseum), and the MIC value was 4.0 µg/mL. In the antifungal and antibacterial assays, compound 2 exhibited significant inhibitory activities

Bisabolanes
Laurecomposin A, laurecomposin B, preintricatol, helianthol B, and gossonorol (1-5, Figure 3) were isolated from the red alga Laurencia tristicha. The complete 1H and 13C NMR assignments of compound 1 were made by a combination of 1H, 13C, DEPT, 1He1H COSY, HSQC, HMBC, and ROESY experiments and the absolute configuration was established by the modified Mosher's method. It was confirmed that compound 1 had activity against Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) SC5314 with MIC values of 26.8 and 16 µg/mL, respectively. Compound 1 also had an obvious inhibitory effect on Microsporum gypseum (M. gypseum), and the MIC value was 4.0 µg/mL. In the antifungal and antibacterial assays, compound 2 exhibited significant inhibitory activities against M. gypseum (Cmccfmza) and moderate activities towards S. aureus, with MIC values of 8 and 15.4 µg/mL, respectively. Compound 3 had inhibitory activity against C. albicans SC5314, S. aureus, and M. gypseum, with MIC values of 32, 13.6, and 8 µg/mL. In addition, compounds 4 and 5 had inhibitory activity against S. aureus and M. gypseum, with MIC values of 4−54 µg/mL [17].
8-Acetoxyl-pathchouli alcohol (70, Figure 5) was isolated from the roots of Valeriana jatamansi Jones, and its antibacterial activity was identified by the micro broth dilution method. The antibacterial assays revealed that compound 70 had a certain inhibitory effect on S. aureus and P. aeruginosa, with MIC values of 128 and 64 µg/mL, respectively [40].
Cryptomeridiol (72, Figure 5), isolated from the seeds of Eugenia jambolana fruit, exhibited inhibitory activity against S. aureus, with a diameter of the inhibitory zone of 8 mm [28].
Xylareremophil and eremophilane mairetolides B and G (81-83, Figure 6) were isolated from the endophytic fungus Xylaria sp. GDG-102, cultured from Sophora tonkinensis. For P. vulgaris and Micrococcus luteum (M. luteum), 81 displayed moderate activity, with the same MIC value of 25 µg/mL, and the MIC values of 83 were 25 µg/mL and 50 µg/mL, respectively. Compound 81 was found to be active against M. luteum with a MIC value of 50 µg/mL. Compounds 81-83 showed inhibitory effects on both B. subtilis and M. lysodeikticus, with a same MIC value of 100 µg/mL [45].

Carotanes
Trichocarotins I-M, CAF-603, 7β-hydroxy CAF-603, trichocarotins E-H, trichocarane A (93-104, Figure 7) were found in the endophytic fungus Trichoderma virens QA-8 in the inner root tissue of mugwort leaves. The antibacterial activities of these compounds were assayed against human pathogens E. coli EMBLC-1 and M. luteus QDIO-3. Each of the compounds showed an inhibitory activity against E. coli, with the MIC values ranging from 0.5 to 32 µg/mL, and the activity of compounds 95-100 and 103 against E. coli, with the same MIC value of 0.5 µg/mL, which was as active as that of the positive control (chloramphenicol, MIC = 0.5 µg/mL). In addition, compounds 94, 97-99, 103, and 104 showed inhibitory activity against M. luteus, with the MIC values ranging from 0.5 to 32 µg/mL. Compound 99 showed potent activity against M. luteus, with MIC values of 0.5 µg/mL, which was stronger than that of chloramphenicol (MIC = 1 µg/mL) [50].

Germacranes
9β-Hydroxyparthenolide-9-O-β-D-glucopyranoside (114, Figure 9) was obtained from the leaves of the Saudi medicinal plant Anvillea garcinii. Compound 114 showed an inhibitory activity against human pathogenic fungi, which was about 80% at 50 µg/mL against C. albicans and C. parapsilosis, with MIC values of 0. 26   Parthenolide (115, Figure 9) was isolated from Asteraceae and Magnoliaceae and is effective against various plant-pathogenic pathogens. The antibacterial assays revealed that compound 115 had a good inhibitory effect on Erwinia amylovora (E. amylovora) and Corynebacterium fascians (C. fascians), with the same MIC value of 20 mg/L. In addition, parthenolide is also effective against V. mali, A. brassicicola, and P. piricola, with EC 50 values of 5, 2, and 5 mg/L, respectively [52]. Parthenolide (115, Figure 9) was isolated from Asteraceae and Magnoliaceae and is effective against various plant-pathogenic pathogens. The antibacterial assays revealed that compound 115 had a good inhibitory effect on Erwinia amylovora (E. amylovora) and Corynebacterium fascians (C. fascians), with the same MIC value of 20 mg/L. In addition, parthenolide is also effective against V. mali, A. brassicicola, and P. piricola, with EC50 values of 5, 2, and 5 mg/L, respectively [52].
Incomptine A and incompetine B (116 and 117, Figure 9) showed antibacterial activity against Vibrio cholerae (V. cholerae), with MIC values of 0.15 mg/mL and 0.05 mg/mL, respectively. The antibacterial activity of compounds 116 and 117 was better than chloramphenicol, which was used as positive control. This result suggested that 116 and 117 may be potential antibiotics for chloramphenicol-resistant bacteria, especially for V. cholerae [53].
Haagenolide and 1,10-epoxyhaagenolide (118 and 119, Figure 9) are two germacranetype sesquiterpenoids isolated from the dichloromethane extract obtained from the aerial parts of Cotula cinerea. The absolute configuration was assigned by applying the advanced Mosher's method to haagenolide and by X-ray diffraction analysis to 1,10-epoxyhaagenolide. E. faecalis EF-91804, E. faecalis EF-91823, E. faecalis EF-165, and E. faecalis EF-91705 were four clinical bacteria isolated from E. faecalis and used to evaluate the antimicrobial activity of compounds 118 and 119. The results indicated that compound 118 could act against all mentioned E. faecalis above, with the same MIC value of 300 µg/mL. Compound 119 inhibited EF-91804, EF-91823, and EF-165, with the same MIC value of 300 µg/mL, while it only inhibited EF-91705 with a MIC value of 150 µg/mL. Therefore, compounds 118 and 119 can be studied as new antibiotics [27].

Cadinanes
Haagenolide and 1,10-epoxyhaagenolide (118 and 119, Figure 9) are two germacranetype sesquiterpenoids isolated from the dichloromethane extract obtained from the aerial parts of Cotula cinerea. The absolute configuration was assigned by applying the advanced Mosher's method to haagenolide and by X-ray diffraction analysis to 1,10-epoxyhaagenolide. E. faecalis EF-91804, E. faecalis EF-91823, E. faecalis EF-165, and E. faecalis EF-91705 were four clinical bacteria isolated from E. faecalis and used to evaluate the antimicrobial activity of compounds 118 and 119. The results indicated that compound 118 could act against all mentioned E. faecalis above, with the same MIC value of 300 µg/mL. Compound 119 inhibited EF-91804, EF-91823, and EF-165, with the same MIC value of 300 µg/mL, while it only inhibited EF-91705 with a MIC value of 150 µg/mL. Therefore, compounds 118 and 119 can be studied as new antibiotics [27].

Farnesanes
9-Hydroxynerolidol and 9-oxonerolidol (129 and 130, Figure 11), possessing chainlike structures, are two farnesane-type sesquiterpenoids isolated from Chiliadenus lopadusanus. The difference between compounds 129 and 130 is that the C-9 hydroxyl group of 129 is oxidized in 130. In the antibacterial experimental assay, 129 exhibited antibacterial activity against Acinetobacter baumannii (A. baumannii) and S. aureus, with MIC values Arteannuin B (128, Figure 10) was isolated from Leonurus japonicus with a significant inhibitory effect on E. coli and E. aerogenes with the MIC values of 25 µg/mL and 50 µg/mL, respectively, by assaying the micro-dilution method [56].
Farnesal (133, Figure 11) was isolated from the n-hexane fraction of the crude acetone extract from the leaves of the Australian Plant Eremophila lucida and showed antibacterial activity against S. aureus ATCC 25923 and S. aureus ATCC 29213, with the same MIC value of 65 µg/mL (195 µM) [59].

Chamigranes
The herb of Leonurus japonicus is a type of traditional Chinese medicine that contains a large number of secondary metabolites. It was often used to regulate menstruation and promote blood circulation. One sesquiterpenoid, named chamigrenal (136, Figure 12), was isolated and studied for its antibacterial activities by the microdilution method. The results showed that compound 136 had antibacterial activity against E. coli, E. aerogenes, Macrococcus caseolyticus (M. caseolyticus), S. auricularis, and S. aureus, and the MIC value was in the range from 25 to 200 µg/mL [56]. 2,10β-Dibromochamigra-2,7-dien-9α-ol, prepacifenol epoxide, compositacin N, and pacifenediol (137−140, Figure 12  Farnesal (133, Figure 11) was isolated from the n-hexane fraction of the crude acetone extract from the leaves of the Australian Plant Eremophila lucida and showed antibacterial activity against S. aureus ATCC 25923 and S. aureus ATCC 29213, with the same MIC value of 65 µg/mL (195 µM) [59].

Pseudoguaiane
Five sesquiterpenoids were isolated from chloroform extract of Ambrosia maritima, including neoambrosin, damsinic acid, damsin, ambrosin, and hymenin (141-145, Figure 13). The antibacterial assays showed that these five sesquiterpenoids had certain antibacterial effects against two plant pathogenic bacteria, Agrobacterium tumefaciens (A. tumefaciens) and E. carotovora, with MIC values ranging from 90 to 520 mg/L. Compound 141 was the most effective against A. tumefaciens and E. carotovora, with MIC values of 150 and 90 mg/L, respectively. In addition, compound 145 caused significant activation of E. carotovora enzymes [61].

Pseudoguaiane
Five sesquiterpenoids were isolated from chloroform extract of Ambrosia maritima, including neoambrosin, damsinic acid, damsin, ambrosin, and hymenin (141-145, Figure  13). The antibacterial assays showed that these five sesquiterpenoids had certain antibacterial effects against two plant pathogenic bacteria, Agrobacterium tumefaciens (A. tumefaciens) and E. carotovora, with MIC values ranging from 90 to 520 mg/L. Compound 141 was the most effective against A. tumefaciens and E. carotovora, with MIC values of 150 and 90 mg/L, respectively. In addition, compound 145 caused significant activation of E. carotovora enzymes [61].

Pseudoguaiane
Five sesquiterpenoids were isolated from chloroform extract of Ambrosia maritima, including neoambrosin, damsinic acid, damsin, ambrosin, and hymenin (141-145, Figure  13). The antibacterial assays showed that these five sesquiterpenoids had certain antibacterial effects against two plant pathogenic bacteria, Agrobacterium tumefaciens (A. tumefaciens) and E. carotovora, with MIC values ranging from 90 to 520 mg/L. Compound 141 was the most effective against A. tumefaciens and E. carotovora, with MIC values of 150 and 90 mg/L, respectively. In addition, compound 145 caused significant activation of E. carotovora enzymes [61].

Drimanes
Two new sesquiterpenoids named ustusoic acid A and B (146 and 147, Figure 14 Two new sesquiterpenoids named ustusoic acid A and B (146 and 147, Figure 14) were isolated from Aspergillus ustus. These compounds had a weak inhibitory effect on vancomycin-resistant Enterococcus faecium (E. faecium) ATCC 700221 and B. subtilis ATCC 49343 . Compounds 146 and 147 had a weak effect on B. subtilis ATCC 49343 and vancomycin-resistant E. faecium ATCC 700221, with MIC values ranging from 38 to 128 µg/mL, respectively [62]. (1S,5S,7S,10S)-Dihydroxyconfertifolin (148, Figure 14) was obtained from Talaromyces purpureogenu residing inside the plant Panax notoginseng, which had an inhibitory effect on E. coli with the MIC value of 25 µM/L [63]. 13-Hydroxylmacrophorin A (149, Figure 14) was isolated from the endophyte Microdiplodia sp. TT-12. Compound 149 had weak activity against R. quercivora, whereas it showed moderate antimicrobial activity against both P. aeruginosa ATCC 15442 and S. aureus NBRC 13276. The results implied that compound 149 is an ingredient that has an antimicrobial against R. quercivora JCM 11526, with an inhibitory area of 12 mm in the culture of Microdiplodia sp. TT-12, which was isolated from the plant hosts [49].

Aromadendrane
Aromadendrane-4β,10α-diol, aromadendrane-4α,10α-diol, and 1-epimer-aromadendrane-4β,10α-diol (150-152, Figure 15) were isolated from Cassia buds, the immature fruits of Cinnamomum cassia (Lauraceae), and their antibacterial activity was evaluated. Compound 151 showed selective inhibitory activities against S. aureus, with an inhibitory zone diameter of 8 mm, while it had no activity against C. albicans and E. coli. Compound 150 exhibited inhibitory effects against C. albicans, S. aureus, and E. coli, and the inhibitory zone diameters were 10, 7, and 10 mm, respectively. Compound 152 not only inhibited the proliferation of C. albicans but also inhibited the proliferation of S. aureus, with inhibitory zone diameters of 10 and 8 mm, respectively [30].  Figure 14) was isolated from the endophyte Microdiplodia sp. TT-12. Compound 149 had weak activity against R. quercivora, whereas it showed moderate antimicrobial activity against both P. aeruginosa ATCC 15442 and S. aureus NBRC 13276. The results implied that compound 149 is an ingredient that has an antimicrobial against R. quercivora JCM 11526, with an inhibitory area of 12 mm in the culture of Microdiplodia sp. TT-12, which was isolated from the plant hosts [49].

Illudalanes
The antibacterial activity and cytotoxicity of incarnatin A, incarnatin B, and incarnolactone C (159-161, Figure 18), which were isolated from the mushroom Gloeostereum incarnatum BCC41461, were tested. Compound 161 exhibited anti-B. cereus activity, with a MIC value of 25 µg/mL, while the MIC values of compounds 159 and 160 were both more than 25 µg/mL [66].

Oplopananes
Two new sesquiterpenoids were isolated from the ethyl acetate extract of Chimonanthus praecox link, named chimonols A and B (162 and 163, Figure 19). The antimicrobial

Illudalanes
The antibacterial activity and cytotoxicity of incarnatin A, incarnatin B, and incarnolactone C (159-161, Figure 18), which were isolated from the mushroom Gloeostereum incarnatum BCC41461, were tested. Compound 161 exhibited anti-B. cereus activity, with a MIC value of 25 µg/mL, while the MIC values of compounds 159 and 160 were both more than 25 µg/mL [66].

Illudalanes
The antibacterial activity and cytotoxicity of incarnatin A, incarnatin B, and incarnolactone C (159-161, Figure 18), which were isolated from the mushroom Gloeostereum incarnatum BCC41461, were tested. Compound 161 exhibited anti-B. cereus activity, with a MIC value of 25 µg/mL, while the MIC values of compounds 159 and 160 were both more than 25 µg/mL [66].

Oplopananes
Two new sesquiterpenoids were isolated from the ethyl acetate extract of Chimonanthus praecox link, named chimonols A and B (162 and 163, Figure 19). The antimicrobial activities of these two compounds were evaluated and the minimum inhibitory concen-

Oplopananes
Two new sesquiterpenoids were isolated from the ethyl acetate extract of Chimonanthus praecox link, named chimonols A and B (162 and 163, Figure 19). The antimicrobial activities of these two compounds were evaluated and the minimum inhibitory concentrations (MICs) were determined by the broth microdilution method in 96-well culture plates. The results suggested that compounds 162 and 163 had a weak antibacterial effect on S. aureus ATCC 6538 and S. aureus ATCC 25923, and the MIC values were 158.2-223.8 µg/mL. Compounds 162 and 163 were inactive against M. tuberculosis, with MIC values being greater than 250 µg/mL [67].

Oplopananes
Two new sesquiterpenoids were isolated from the ethyl acetate extract of Chimonanthus praecox link, named chimonols A and B (162 and 163, Figure 19). The antimicrobial activities of these two compounds were evaluated and the minimum inhibitory concentrations (MICs) were determined by the broth microdilution method in 96-well culture plates. The results suggested that compounds 162 and 163 had a weak antibacterial effect on S. aureus ATCC 6538 and S. aureus ATCC 25923, and the MIC values were 158.2-223.8 µg/mL. Compounds 162 and 163 were inactive against M. tuberculosis, with MIC values being greater than 250 µg/mL [67]. 8-β-p-Coumaroyl-oplopanone (164, Figure 19) was isolated from the ethanol extract of the whole herbs of Pilea cavaleriei. An antibacterial experiment revealed that compound 164 had anti-tuberculosis activity, and the MIC value was 16 µg/mL [68]. 8-β-p-Coumaroyl-oplopanone (164, Figure 19) was isolated from the ethanol extract of the whole herbs of Pilea cavaleriei. An antibacterial experiment revealed that compound 164 had anti-tuberculosis activity, and the MIC value was 16 µg/mL [68].

Others
Three sesquiterpenoids were isolated from a Vietnamese marine sponge of Spongia sp. and named as langconols A and C and langcoquinone C (171-173, Figure 22), respectively. The antibacterial assays of these isolates suggested that 171 and 172 possessed significant antibacterial activities against B. subtilis, with MIC values of 12.5 and 25 µM, and 173 also had good inhibitory effects against B. subtilis and S. aureus, with MIC values of 6.25 and 12.5 µM, respectively [71]. Compound 174 (Figure 22), named 4-epi-15-hydroxyacorenone, from Chinese agarwood, could inhibit the proliferation of S. aureus and R. solanacearum, with inhibitory zones of 12.35 and 16.9 mm [48]. Two sesquiterpenoids, dysoxyphenol and 7R,10S-2-hydroxycalamenene (175 and 176, Figure 22), were isolated from the acetone extract of Dysoxylum densiflorum seeds. Both compounds had significant antibacterial properties against B. subtilis (MIC = 28 µM) which were better than those of the positive control amoxicillin (MIC = 34 µM). Compounds 175 and 176 were also evaluated for their antifungal properties against two wood-rotting fungi (brown rot, F. palustris; white rot, T. versicolor) using a zone inhibition assay at two concentrations (0.46 and 4.58 mM). Compound 175 showed the same antifungal effect to both fungi at both concentrations. Compound 176 was able to inhibit the growth of white-rot fungi but not brown-rot fungi at the concentration of 0.46 mM and inhibited both fungi at a higher concentration (4.58 mM) [72].

Others
Three sesquiterpenoids were isolated from a Vietnamese marine sponge of Spongia sp. and named as langconols A and C and langcoquinone C (171-173, Figure 22), respectively. The antibacterial assays of these isolates suggested that 171 and 172 possessed significant antibacterial activities against B. subtilis, with MIC values of 12.5 and 25 µM, and 173 also had good inhibitory effects against B. subtilis and S. aureus, with MIC values of 6.25 and 12.5 µM, respectively [71]. Compound 174 (Figure 22), named 4-epi-15-hydroxyacorenone, from Chinese agarwood, could inhibit the proliferation of S. aureus and R. solanacearum, with inhibitory zones of 12.35 and 16.9 mm [48]. Two sesquiterpenoids, dysoxyphenol and 7R,10S-2-hydroxycalamenene (175 and 176, Figure 22), were isolated from the acetone extract of Dysoxylum densiflorum seeds. Both compounds had significant antibacterial properties against B. subtilis (MIC = 28 µM) which were better than those of the positive control amoxicillin (MIC = 34 µM). Compounds 175 and 176 were also evaluated for their antifungal properties against two wood-rotting fungi (brown rot, F. palustris; white rot, T. versicolor) using a zone inhibition assay at two concentrations (0.46 and 4.58 mM). Compound 175 showed the same antifungal effect to both fungi at both concentrations. Compound 176 was able to inhibit the growth of white-rot fungi but not brown-rot fungi at the concentration of 0.46 mM and inhibited both fungi at a higher concentration (4.58 mM) [72].  [73]. Genus Laurencia is often studied by researchers, and it has large number of non-secondary metabolites. Two sesquiterpenoids were isolated from Bornean Laurencia snapeyi, including snakeol and snakediol (183 and 184, Figure 22). Researchers tested the antibacterial activity of the two compounds by the microdilution method. The result revealed that compounds 183 and 184 showed strong antibacterial activity against E. coli, with MIC/MBC ratios of 3.02 and 2.76, respectively [64].
Two compounds named penicibilaenes A and B (185 and 186, Figure 22) were obtained from the marine isolate of Penicillium bilaiae MA-267. Both compounds have selective inhibitory effects on C. gloeosporioides, with MIC values of 1.0 and 0.125 µg/mL, respectively [75].
New sesquiterpenoid lactones, zinaflorin VI and the δ-elemenolide juniperin (179 and 180, Figure 22), were isolated from Zinnia peruviana L. The MICs of 179 on B. subtilis and S. aureus were 32 and 64 µg/mL, respectively, and the MICs were 4 and 8 µg/mL for compound 180 while the α-Glucosidase inhibition was not active [74].  [73]. Genus Laurencia is often studied by researchers, and it has large number of non-secondary  [67].
Researchers tested the antibacterial activity and cytotoxicity of (E)-dictyochromenol (192, Figure 22), which was isolated from the brown alga Dictyopteris undulate Holmes. The result found was that compound 192 displayed anti-B. cereus activity, with a MIC value of 1.56 µg/mL [66]. An antibacterial sesquiterpenoid compound from Elephantopus tomentosus, named tomenphantopin H (193, Figure 22), was isolated, possessing an inhibitory effect on S. aureus, with a diameter of the inhibition zone of 14.2 mm, while the diameter of the inhibition zone of the positive control, Kanamycin sulfate, was 32.6 mm [76].
Two compounds, cinnamosim A and 1β,7-dihydroxyl opposite-4(15)-ene (194 and 195, Figure 22), were isolated from Cassia buds, the immature fruits of Cinnamomum cassia (Lauraceae). The antibacterial activities of compounds 194 and 195 were evaluated. The result was that compound 194 and 195 selectively inhibited the proliferation of C. albicans, with inhibitory zone diameters of 11 and 8 mm, respectively, at the concentration of 300 µg/disk. Compound 195 could also inhibit the proliferation of S. aureus, with inhibitory zone diameters of 7 mm at the same concentration [30]. 10-Hydroxy-7,10-epoxysalvialane (196, Figure 22) with antibacterial effects was obtained from Alisma orientale and could inhibit S. aureus, with a MIC value of 100 mg/mL [31].
Clovane-2β,9α-diol (200, Figure 22) was isolated from Eugenia jambolana seeds. It was found that compound 200 had inhibitory activity against S. aureus, with inhibitory zone diameters of 10 mm at the concentration 100 µg/disk. [28]. Debromolaurinterol (201, Figure 22) was isolated from the red algae Laurencia snackeyi. The antibacterial activity of compound 201 was tested by the microdilution method. The result found was that compound 201 showed strong antibacterial activity against S. typhi, with a MIC/MBC ratio of 2.79 [64].

Mechanisms of Antimicrobial Action by Sesquiterpenoids
The mechanisms of antibiotics against bacteria mainly include affecting cell wall synthesis (β-lactams) and disrupting bacterial membranes, interacting with ribosomal subunits (Tetracycline, Chloramphenicol, Aminoglycosides, etc), disrupting nucleic acid action (Rifampicin, Fluoroquinolones), and interfering with metabolic pathways (Folic acid analogs, sulfonamides) [81]. The corresponding mechanism of antibacterial resistance ranges from accelerating antibiotic efflux through bacterial efflux pumps; alteration of the bacterial porins' structure, which decreases bacterial permeability to antibiotic influx; and destruction of antibacterial agents by hydrolytic enzymes to alteration of binding sites for antibiotics [82].
The mechanism of sesquiterpenoids against bacteria has not been clearly reported, but it is believed that the microbial cell membranes play an important role. Bacterial subpopulations which are characterized by low metabolism could reduce absorption of antibiotics, especially for the active molecules on the cell wall such as beta-lactams and glycopeptides, making it difficult to treat infections. The mechanism by which the sesquiterpenoids can inhibit the microorganisms involves different modes of action; one which researchers basically agree with is that sesquiterpenoids can destabilize microbial cell membranes. Because the bacterial cell wall is highly lipophilic, it means that a certain lipophilicity is necessary for antibiotics to function [83]. The hydrophobicity of some sesquiterpenoids disturbs the cytoplasmic membrane or compounds in it, such as some classes of proteins, increasing the ionic permeability and causing cytoplasmic extravasation and, as consequence, cellular lysis, as well as interfering with the activity of the respiratory current and energy production. Terpenes isolated from essential oils, such as thymol and carvacrol, may act as permeabilizers of the cell membrane, increasing the entry of antibiotics [54]. Thus, α-bisabolol is possibly responsible for the antibacterial and synergic action when associated with antibiotics. Lipophilic sesquiterpenoids can destroy the membrane and cause ion leakage in the membrane. The results showed that the action mode of β-caryophyllene is to damage the cell membrane and produce non-selective pores, causing the leakage of substances in the cells, and finally causing cell death [84]. Farnesal and farnesol have previously been reported to have antimicrobial activity. Farnesol exerts antibacterial activity by disrupting the cell membrane, and it was also found that it can destroy biofilms of Gram-positive bacteria by reducing biomass [59]. Although the mechanisms responsible for the antibacterial activity of farnesal have not yet been reported, it appears reasonable to hypothesize that farnesal could act in the same way as farnesol, possibly by its hydrophobic nature facilitating insertion into the bacterial phospholipid bilayer membrane and consequent structural disruption. Interestingly, bacteria are able to decrease the concentration of antibiotics in their own cells through the overexpression of efflux pumps. In a mechanistic study, Fazly Bazzaz et al. showed that galbanic acid modulated the resistance in clinical drug-resistant isolates of S. aureus via the inhibition of the efflux pump [85].
The main mechanisms of antifungal effects concern interfering substance transport, yeast-to-hypha transition, host immunity, redox, and others [86]. For instance, polygodial is a sesquiterpenoid dialdehyde that can inhibit fungi. M. V. Castelli et al. carried out experiments using mammalian mitochondrial preparations. The results support the claim that that polygodial mainly plays a role in inhibiting ATP synthesis because the ATP synthesis of phosphorylating submitochondrial Mg + -ATP particles is inhibited at the concentration of polymers similar to the MIC values reported by several yeasts and filamentous fungi [87,88].
Natural products with good inhibitory activity against both bacteria and fungi have broad application prospects in the future development of antifungal drugs. Therefore, it is necessary to clear the mechanisms of action and find antimicrobial targets while exploring new antimicrobial agents.

Structure-Activity Relationship
In this review, the structure-activity relationship of compounds with antibacterial activities was analyzed. The compounds with eremophilane, xanthane, lindenane, farnesane, guaiane, penicibilaene, germacrene, daucane, carotene, and illudalane-type skeleton showed relatively strong antibacterial activity (MIC values were lower than 50 µg/mL). Among these types, differences in substituents, different substitution sites, and configuration lead to various degrees of bacteriostatic effect.
Compound 21 had good antibacterial activity against T. rubrum, while compound 22 showed no activity. Apart from C6-OH, compounds 21 and 22 both had a bisabolane skeleton, which may prove the importance of C6-OH in the inhibition of this kind of fungi. Compounds 28-34 all have a similar guaiane skeleton. Comparing the antibacterial activity in pairs, compounds 31, 33, and 34 with C4-OH had strong activity for a variety of pathogenic bacteria, while other compounds without this group had slightly lower antibacterial activity. It seems that C4-OH increased antibacterial activity. In the antibacterial experiment, 71 and 72 are both active against S. aureus, with 71 being more potent than 72. The difference in structures is that the C-9 hydroxyl of 71 was oxidized in 72, which may influence the activity. For farnesanes-type sesquiterpenoids, compound 73 was more active against aquatic and human pathogens than compound 74, but less active against the plant pathogenic fungus, which may be due to the different oxidation degrees of the compounds under C-11. For pseudoguaianes-type sesquiterpenoids, the inhibitory effects of 141 on A. tumefaciens and E. carotovora were stronger than those of 142. The structures of 142 did not have double bonds at C2 and C3, comparing it with 141, which suggested that the double bonds on C-2 and C-3 may increase the antibacterial activity.

Conclusions
A total of 205 sesquiterpenoids with antibacterial and antifungal activity, which were found and tested from 2012 to 2022, were mainly included in 19 carbon skeleton types, and the number of guaiane sesquiterpenoids was the largest. The names, sources, and chemical structures of 205 sesquiterpenoids are listed in this review. The structure-activity relationship of active compounds is also discussed. According to the data above, we can derive some potential molecules with good antibacterial and antifungal activity. Compound 100 is considered as a potential antimicrobial compound against E. coli, with a MIC

Conclusions
A total of 205 sesquiterpenoids with antibacterial and antifungal activity, which were found and tested from 2012 to 2022, were mainly included in 19 carbon skeleton types, and the number of guaiane sesquiterpenoids was the largest. The names, sources, and chemical structures of 205 sesquiterpenoids are listed in this review. The structure-activity relationship of active compounds is also discussed. According to the data above, we can derive some potential molecules with good antibacterial and antifungal activity. Compound 100 is considered as a potential antimicrobial compound against E. coli, with a MIC of 0.5 µg/mL. Compounds 114 and 134 were most potent against B. licheniformis, with MIC values of 3.1 and 2.3 µg/mL, respectively. Furthermore, compounds 114 and 31 also exhibited an effect on C. albicans, with MICs of 0.26 and 0.21 µg/mL, respectively. Compound 122 showed a striking inhibition of F. oxysporum. F. sp. Cucumebrium and B. sorokiniana, with the same MIC value of 1 µg/mL. As for B. subtilis, compound 180 showed a strong activity (MIC = 4 µg/mL). Compound 192 had a strong effect on B. cereus (MIC = 1.56 µg/mL). The above conclusions were drawn by reviewing large number of sesquiterpenoids and comparing the antimicrobial activities of different structures. The structure-activity relationship plays a key role in modern chemical synthesis and will help people synthesize more effective sesquiterpenoids and use safe natural compounds as antibacterial agents in overcoming bacteria, fungi, and the challenge of drug resistance. These sesquiterpenoids may have the most potential as new natural antibacterial compounds. It is hoped that this review will provide support for the discovery of active drug lead molecules.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/biom12091271/s1, The Mol. files of sesquiterpenoids with antibacterial and antifungal activity; Table S1: Abbreviations of bacteria and fungi; Table S2: Compounds with antibacterial and antifungal effects. Table S3: Compounds with antibacterial and antifungal effects.