Identification of Antibacterial Metabolites from Endophytic Fungus Aspergillus fumigatus, Isolated from Albizia lucidior Leaves (Fabaceae), Utilizing Metabolomic and Molecular Docking Techniques
Abstract
:1. Introduction
2. Results
2.1. Endophytic Fungi Isolation and Cultivation
2.2. Identification of the Fungus Based on Phenotypic and Genotypic Characteristics
2.3. UHPLC–QTOF Analysis of A. fumigatus Ethyl Acetate Extract
2.4. Isolation and Characterization of the Metabolites
2.5. Biological Activity
2.5.1. Antimicrobial Activity
2.5.2. In Vitro Enzyme Assessment
2.6. Molecular Modeling Study
3. Discussion
4. Materials and Methods
4.1. Plant Collection and Identification
4.2. Surface Sterilization and Isolation of Endophytic Fungi
4.3. Morphological and Taxonomic Identification of the Fungus
4.4. Scale-Up Fermentation and Extraction
4.5. UHPLC-QTOF-MS/MS Profiling of the Fungal Crude Extract
4.6. Fractionation and Purification of Metabolites
4.7. Screening of Antimicrobial Activity
4.7.1. Agar Disc Diffusion Method
4.7.2. Microplate Dilution Method
4.7.3. In Vitro Enzyme Assessment
4.8. Molecular Docking Study
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | Rt (min) | Name | Ion m/z ppm | Molecular Formula | Fragmentation | Ref | |
---|---|---|---|---|---|---|---|
Positive | Negative | ||||||
1 | 1.92 | Cyclo-(Leu-Pro) | 211.1411 | C11H19N2O2 [M + H]+ | 197.1263 183.1469 | [19] | |
2 | 2.41 | Cyclo-(Phe-Pro) | 245.1266 | C14H17N2O2 [M + H]+ | 217.1298 154.0699 120.0771 | [20] | |
3 | 2.49 | Isosclerone | 357.2144 | C20H21O6 [2M + H]+ | 339.2029 297.1932 243.1441 | [21] | |
4 | 3.05 | 9-Deacetylfumigaclavine C | 325.2252 | C21H29N2O [M + H]+ | 307.2153 238.1444 | [22] | |
5 | 3.08 | Cyclotryprostatin A | 410.1730 | C22H24N3O5 [M − H]− | 308.1407 293.1173 | [23] | |
6 | 3.30 | Fumigaclavine B | 255.0293 | C16H19N2O [M − H]− | 237.0181 227.0344 211.0392 | [24] | |
7 | 3.32 | Fumigatoside F |
421.1488 | C22H21N4O5 [M + H]+ | 403.1451 286.0980 199.0497 120.0442 | [25] | |
8 | 3.35 | Pseurotin A | 454.1460 | C22H25NO8Na [M + Na]+ | 421.1453 316.0744 273.0687 | [26] | |
9 | 3.52 | Spirotryprostatin A | 396.3100 | C22H26N3O4 [M + H]+ | 340.1292 215.0815 | [23] | |
10 | 3.60 | Hexylitaconic Acid | 213.1128 | C11H17O4 [M − H]− | 195.1015 169.1230 151.1132 | [27] | |
11 | 3.61 | Fumigaclavine C | 367.2376 | C23H31O2N2 [M + H]+ | 307.2177 276.1752 238.1470 | [26] | |
12 | 3.64 | 6-Methoxyspirotryprostatin B (Spirotryprostatin G) | 394.1744 | C22H24N3O4 [M + H]+ | 269.1280 241.0602 213.0659 | [28] | |
13 | 3.71 | Tryptoquivaline F | 403.1399 | C22H19N4O4 [M + H]+ | 239.0816 211.0865 199.0502 171.0553 147.0551 | [29] | |
14 | 3.71 | Chaetominine | 401.1257 | C22H17N4O4 [M − H]− | 383.1139 237.0649 145.0400 | [30] | |
15 | 3.74 | 9-Deacetoxyfumigaclavine C | 309.2312 | C21H29N2 [M + H]+ | 278.1869 208.1018 | [22] | |
16 | 3.86 | Synerazol | 414.1528 | C22H24NO7 [M + H]+ | 221.0789 105.0323 77.0368 | [31] | |
17 | 4.10 | Azaspirofurans B | 398.1227 | C21H20NO7 [M + H]+ | 219.0641 105.0320 | [32] | |
18 | 4.15 | Monomethylsulochrin-4-sulphate | 425.0542 | C18H17O10S [M − H]− | 345.0978 313.0711 181.0503 | [33] | |
19 | 4.27 | Fumagiringillin | 475.2341 | C26H35O8 [M − H]− | 149.0601 131.0498 105.0708 97.0657 | [34] | |
20 | 4.32 | Questin | 283.0607 | C16H11O5 [M − H]− | 283.0613 268.0373 240.0431 | [26] | |
21 | 4.35 | Fumitremorgin B | 462.2388 | C27H31N3O4 [M−H2O + H]+ | 394.1750 319.1750 277.1282 | [26] | |
22 | 4.38 | Pyripyropene A | 584.2496 | C31H38NO10 [M + H]+ | 506.2165 202.0495 148.0389 | [35] | |
23 | 4.43 | Azaspirofurans A | 412.1392 | C22H22NO7 [M + H]+ | 219.0587 105.0273 | [32] | |
24 | 4.44 | Monomethyl sulochrin | 345.0978 | C18H17O7 [M − H]− | 313.0654 181.0446 166.0209 | [29] | |
25 | 4.45 | Methylorsilinate | 181.0503 | C9H9O4 [M − H]− | 138.0318 122.0369 123.0083 | [36] | |
26 | 4.55 | Fumitremorgin C | 380.1122 | C22H26N3O3 [M + H]+ | 412.1327 380.1072 324.2825 | [26] | |
27 | 4.65 | Ethylα-D-glucopyranoside | 209.0408 | C8H17O6 [M + H]+ | 181.0446 165.0503 | [37] | |
28 | 4.84 | Emodin | 269.0450 | C15H9O5 [M − H]− | 241.0508 225.0558 197.0603 | [38] | |
29 | 4.96 | 6,16-O-Dideacetyl helvolic acid 21,16-lactone | 467.2767 | C29H39O5 [M + H]+ | 468.2348 449.2682 421.2722 135.0777 | [39] | |
30 | 5.26 | 16-O-Deacetylhelvolic acid 21,16-lactone | 509.2873 | C31H41O6 [M + H]+ | 449.2567 322.2983 268.2873 135.0684 | [39] | |
31 | 5.26 | Helvolic acid | 567.2966 | C33H43O8 [M − H]− | 525.2847 463.2842 403.2631 217.1227 | [26] | |
32 | 5.44 | 16-O-propionyl-16-O-deacetylhelvolic acid/ 6-O-propionyl-6-O-deacetylhelvolic acid | 581.3124 | C34H45O8 [M − H]− | 567.2964 441.2527 397.2271 311.1687 293.2122 | [39] | |
33 | 5.45 | 6-O-propionyl-6,16-O-dideacetylhelvolic acid21,16-lactone |
523.3043 | C32H43O6 [M + H]+ | 449.2689 403.2631 135.0807 | [39] | |
34 | 5.51 | Pyripyropene F | 466.2596 | C28H36NO5 [M + H]+ | 392.2209 202.0500 148.0390 | [40] | |
35 | 5.65 | Pyripyropene O | 508.3419 | C29H34NO7 [M − H]− | 464.3519 377.3212 115.0031 73.0296 | [41] | |
36 | 6.09 | Linoleic acid | 279.2324 | C18H31O2 [M − H]− | 279.2325 261.2223 | [42] | |
37 | 6.34 | Oleic acid | 281.2484 | C18H33O2 [M − H]− | 263.2366 240.9990 | [43] | |
38 | 6.37 | 5,8-Epidioxyergosta-6,9(11),22-trien-3-ol | 427.2474 | C28H43O3 [M + H]+ | 409.3046 381.3149 363.2885 267.1719 147.0028 | [44] | |
39 | 6.82 | Ergosterol peroxide | 429.3734 | C28H45O3 [M + H]+ | 411.3615 393.3512 341.0154 | [44] | |
40 | 6.90 | (22E)-Ergosta4,6,8(14), 22,24(28)-pentaen-3-one | 391.3007 | C28H39O [M + H]+ | 267.1748 149.0235 69.0703 | [45] | |
41 | 7.29 | Ergosta4,6,8(14),22-tetraen-3-one | 393.3165 | C28H41O [M + H]+ | 268.1830 253.1595 | [46] | |
42 | 7.54 | Ergosterol | 397.3822 | C28H45O [M + H]+ | 395.3319 377.3214 | [26] |
Test Microrganisms | Zone of Inhibition (ZI, mm) and Minimum Inhibitory Concentration (MIC, µg/mL) | |||||
---|---|---|---|---|---|---|
Ethyl Acetate Extract | Ciprofloxacin | Nystatin | ||||
ZI | MIC | ZI | MIC | ZI | MIC | |
S. aureus | 23.07 ± 0.51 | 7.81 | 36.90 ± 0.36 | 0.63 | - | - |
B. subtilis | 10.63 ± 0.25 | 31.25 | 41.63 ± 0.93 | 0.31 | - | - |
E. coli | 6.37 ± 0.32 | 62.50 | 35.40 ± 0.53 | 1.25 | - | - |
P. aeruginosa | NA | 125.00 | 30.87 ± 0.35 | 2.50 | - | - |
P. vulgaris | 14.37 ± 0.47 | 15.63 | 34.50 ± 0.40 | 1.25 | - | - |
C. albicans | 17.13 ± 0.55 | 15.63 | - | - | 30.27 ± 0.25 | 2.50 |
A. niger | NA | 125.00 | - | - | 22.27 ± 0.25 | 5.00 |
Compounds | Zone of Inhibition (ZI, mm) | Minimum Inhibitory Concentration (MIC, µg/mL) |
---|---|---|
Ergosterol | 14.10 ± 0.30 | 15.63 |
Ergosterol Peroxide | NA | NA |
Helvolic acid | 33.00 ± 0.95 | 1.95 |
Pseurotin A | 10.83 ± 0.21 | 31.25 |
Monomethyl sulochrin | 9.90 ± 0.20 | 31.25 |
Isosclerone | NA | NA |
Monomethyl sulochrin-4-sulphate | 26.56 ± 0.51 | 3.91 |
Chaetominine | NA | NA |
Ciprofloxacin | 36.90 ± 0.36 | 0.63 |
Sample | IC50 (M ± S.D.) (µg/mL) | |
---|---|---|
DNA Gyrase | Topoisomerase IV | |
Ethyl acetate extract | 0.86 ± 0.05 | 1.23 ± 0.07 |
Ciprofloxacin | 0.51 ± 0.03 | 2.15 ± 0.12 |
S. aureus DNA Gyrase | ||||
---|---|---|---|---|
Compounds | Docking Score (Kcal/mol) | Amino Acid Residues (Bond Length A°) | Atoms of Compound | Type of Bond |
Ciprofloxacin | −7.22 | Ser1084(2.79); DG9; DG9 | O(OH)(COOH); N(quinoline); Pyridine(quinoline) | H-acc Arene-cation Arene-arene |
Ergosterol | −7.40 | Asp1083(2.76); Asp1083(2.78); Ser1084(2.82); Ser1084(3.13) | O(OH); O(OH); O(OH); O(OH) | H-acc H-acc H-acc H-acc |
Helvolic acid | −8.83 | Asp508(3.38); Leu583(2.47); Gly584(2.89); His1081(2.70); Ser1085(2.72) | H(OH); O(OH); O(OH); O(CO at p-7); O(CO)(acetoxy at p-6) | H-don H-acc H-acc H-acc H-acc |
Monomethyl sulochrin-4- sulphate | −7.79 | Asp437(2.65); Ser438(2.48); Asp1083(2.99); Asp1083(3.46); Ser1084(3.02); Ser1084(2.54) Ser1084(2.85) DG9(2.38) | O(OH)(phenol); O(OH)(phenol); O(S=O)(OSO3H); H(OSO3H); O(S=O)(OSO3H); O(OH)(OSO3H); O(OH)(OSO3H); O(CO)(benzoyl) | H-acc H-acc H-don H-don H-acc H-acc H-acc H-acc |
S. aureus Topoisomerase IV | ||||
---|---|---|---|---|
Compounds | Docking Score (Kcal/mol) | Amino Acid Residues (Bond Length A°) | Atoms of Compound | Type of Bond |
Novobiocin | −7.60 | Asn49(3.30); Asp76(2.04); Arg138(3.11); Pro82 | H(OH)(oxan-4-yl); H(OCONH2); O(CO)(coumarin); C6H2(coumarin) | H-don H-don H-acc Arene-cation |
Ergosterol | −7.92 | Arg79(2.62); Arg138(3.11) | O(OH); O(OH) | H-acc H-acc |
Helvolic acid | −8.43 | Asn49(1.57); Asn49(2.86); Asn49(3.05); Asp52(3.01) | H(OH)(COOH); O(CO)(COOH); O(CO)(COOH); O(CO)(COOH) | H-don H-don H-don H-don |
Monomethyl sulochrin-4-sulphate | −8.25 | Asn49(3.59); Asp52(2.47); Arg79(2.64); Gly80(2.61); Arg138(2.93); Arg138(2.99) | H(OH)(phenol); H(OH)(phenol); O(OSO3H); O(S=O)(OSO3H); O(S=O)(OSO3H); O(S=O)(OSO3H) | H-don H-don H-acc H-don H-acc H-acc |
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Hussein, M.E.; Mohamed, O.G.; El-Fishawy, A.M.; El-Askary, H.I.; El-Senousy, A.S.; El-Beih, A.A.; Nossier, E.S.; Naglah, A.M.; Almehizia, A.A.; Tripathi, A.; et al. Identification of Antibacterial Metabolites from Endophytic Fungus Aspergillus fumigatus, Isolated from Albizia lucidior Leaves (Fabaceae), Utilizing Metabolomic and Molecular Docking Techniques. Molecules 2022, 27, 1117. https://doi.org/10.3390/molecules27031117
Hussein ME, Mohamed OG, El-Fishawy AM, El-Askary HI, El-Senousy AS, El-Beih AA, Nossier ES, Naglah AM, Almehizia AA, Tripathi A, et al. Identification of Antibacterial Metabolites from Endophytic Fungus Aspergillus fumigatus, Isolated from Albizia lucidior Leaves (Fabaceae), Utilizing Metabolomic and Molecular Docking Techniques. Molecules. 2022; 27(3):1117. https://doi.org/10.3390/molecules27031117
Chicago/Turabian StyleHussein, Mai E., Osama G. Mohamed, Ahlam M. El-Fishawy, Hesham I. El-Askary, Amira S. El-Senousy, Ahmed A. El-Beih, Eman S. Nossier, Ahmed M. Naglah, Abdulrahman A. Almehizia, Ashootosh Tripathi, and et al. 2022. "Identification of Antibacterial Metabolites from Endophytic Fungus Aspergillus fumigatus, Isolated from Albizia lucidior Leaves (Fabaceae), Utilizing Metabolomic and Molecular Docking Techniques" Molecules 27, no. 3: 1117. https://doi.org/10.3390/molecules27031117