{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:08:30Z","timestamp":1792782510735,"version":"4.5.0"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":89,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["CSUR240319209934"],"award-info":[{"award-number":["CSUR240319209934"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"name":"North-West University","id":[{"id":"https:\/\/ror.org\/010f1sq29","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Appl Microbiol Biotechnol"],"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      The escalating threat of multidrug-resistant (MDR) bacterial pathogens underscores the urgent need for novel antimicrobial agents. Here, we combined a one-strain many compounds (OSMAC) and untargeted metabolomics approaches to investigate the bioactivities and the chemical space of the endophytic fungus\n                      <jats:italic>Alternaria alternata<\/jats:italic>\n                      P02PL2, isolated from a medicinal plant,\n                      <jats:italic>Sclerocarya birrea<\/jats:italic>\n                      . The antibacterial activities were assessed against contemporary clinical isolates, MDR\n                      <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                      5625574, methicillin-resistant\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      (MRSA) 5627679, and a collection culture of\n                      <jats:italic>S. aureus<\/jats:italic>\n                      ATCC 25923 for reference. We first tested for bioactivities across eight growth media to optimize the production of bioactive secondary metabolites. The bioactive fungal extract fractions exhibited minimum inhibitory concentrations (MICs) ranging from 0.25 to 0.5\u00a0mg\/mL. This was followed by an untargeted metabolomics analysis, which identified 41 secondary metabolites. Virtual screening, molecular docking, and 200-ns molecular dynamics simulations targeting\n                      <jats:italic>S. aureus<\/jats:italic>\n                      and\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      DNA gyrase revealed lead compounds with superior binding affinities (e.g., fluorescein \u22129.2\u00a0kcal\/mol for\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      ; pyrrolo[1,2-a] pyrazine-1,4-dione, hexahydro \u22128.8\u00a0kcal\/mol for\n                      <jats:italic>S. aureus<\/jats:italic>\n                      ) compared to reference ligands. Binding free energy calculations highlighted strong affinities, with 5,7-dihydroxy-2-(4-hydroxyphenyl)-6,8-bis(3,4,5-trihydroxyoxan-2-yl)chromen-4-one (\u221242.16\u00a0kcal\/mol) and fluorescein (\u221241.42\u00a0kcal\/mol) outperforming the\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      reference ligand evo (\u221219.80\u00a0kcal\/mol) and 80s (\u221248.74\u00a0kcal\/mol) leading for\n                      <jats:italic>S. aureus<\/jats:italic>\n                      . Per-residue energy decomposition and quantum chemical analyses further elucidated key interactions and reactivity profiles. These results position\n                      <jats:italic>A. alternata<\/jats:italic>\n                      P02PL2 as a promising source of DNA gyrase inhibitors to combat antimicrobial resistance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:italic>\u2022\u00a0<\/jats:italic>\n                      <jats:italic>A. alternata extracts inhibits S. aureus and Pseudomonas with MIC of 0.25-0.5 mg\/mL<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>\u2022\u00a0<\/jats:italic>\n                      <jats:italic>Inhibitors included Diketopiperazine (S. aureus), C-glycosyl flavone (Pseudomonas)<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>\u2022\u00a0<\/jats:italic>\n                      <jats:italic>In silico analyses suggest the metabolites putatively inhibit bacterial DNA gyrase<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00253-026-13966-z","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T14:26:12Z","timestamp":1784816772000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Untargeted metabolomics and in silico analysis identifies potential DNA gyrase inhibitors from an endophytic fungus Alternaria alternata P02PL2"],"prefix":"10.1007","volume":"110","author":[{"given":"Aviwe N.","family":"Matandela","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sphamandla E.","family":"Mtambo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonder P.","family":"Nxumalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2323-282X","authenticated-orcid":false,"given":"Sizwe I.","family":"Ndlovu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"13966_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo11070418","author":"AV Aderemi","year":"2021","unstructured":"Aderemi AV, Ayeleso AO, Oyedapo OO, Mukwevho E (2021) Metabolomics: a scoping review of its role as a tool for disease biomarker discovery in selected non-communicable diseases. Metabolites. https:\/\/doi.org\/10.3390\/metabo11070418","journal-title":"Metabolites"},{"issue":"11","key":"13966_CR2","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.2174\/0929867326666190916144709","volume":"27","author":"E Ancheeva","year":"2020","unstructured":"Ancheeva E, Daletos G, Proksch P (2020) Bioactive secondary metabolites from endophytic fungi. Curr Med Chem 27(11):1836\u20131854. https:\/\/doi.org\/10.2174\/0929867326666190916144709","journal-title":"Curr Med Chem"},{"key":"13966_CR3","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/j.trac.2015.08.015","volume":"80","author":"A Andrade-Eiroa","year":"2016","unstructured":"Andrade-Eiroa A, Canle M, Leroy-Cancellieri V, Cerd\u00e0 V (2016) Solid-phase extraction of organic compounds: a critical review (part I). TrAC Trends Anal Chem 80:641\u2013654. https:\/\/doi.org\/10.1016\/j.trac.2015.08.015","journal-title":"TrAC Trends Anal Chem"},{"key":"13966_CR4","doi-asserted-by":"publisher","unstructured":"Aron AT, Gentry EC, McPhail KL, Nothias LF, Nothias-Esposito M, Bouslimani A, Petras D, Gauglitz JM, Sikora N, Vargas F, van Der Hooft JJJ, Ernst M, Bin Kang K, Aceves CM, Caraballo-Rodriguez AM, Koester I, Weldon KC, Bertrand S, Roullier C, \u2026, Dorrestein PC (2020) Reproducible molecular networking of untargeted mass spectrometry data using GNPS. Nat Protoc 15(6):1954\u20131991. https:\/\/doi.org\/10.1038\/s41596-020-0317-5","DOI":"10.1038\/s41596-020-0317-5"},{"key":"13966_CR5","doi-asserted-by":"publisher","DOI":"10.3390\/plants8090350","author":"JA Asong","year":"2019","unstructured":"Asong JA, Amoo SO, McGaw LJ, Nkadimeng SM, Aremu AO, Otang-Mbeng W (2019) Antimicrobial activity, antioxidant potential, cytotoxicity and phytochemical profiling of four plants locally used against skin diseases. Plants. https:\/\/doi.org\/10.3390\/plants8090350","journal-title":"Plants"},{"issue":"8","key":"13966_CR6","doi-asserted-by":"publisher","first-page":"3684","DOI":"10.1063\/1.448118","volume":"81","author":"HJC Berendsen","year":"1984","unstructured":"Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81(8):3684\u20133690. https:\/\/doi.org\/10.1063\/1.448118","journal-title":"J Chem Phys"},{"key":"13966_CR7","volume-title":"Discovery studio modeling environment","author":"DS Biovia","year":"2024","unstructured":"Biovia DS (2024) Discovery studio modeling environment. Dassault Syst, San Diego"},{"issue":"7","key":"13966_CR8","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1002\/1439-7633(20020703)3:7<619::Aid-Cbic619>3.0.Co;2-9","volume":"3","author":"HB Bode","year":"2002","unstructured":"Bode, H. B., Bethe, B., H\u00f6fs, R., & Zeeck, A. (2002). Big effects from small changes:: possible ways to explore nature\u2019s chemical diversity. Chembiochem, 3(7), 619\u2013627. https:\/\/doi.org\/10.1002\/1439-7633(20020703)3:7<619::Aid-Cbic619>3.0.Co;2-9","journal-title":"Chembiochem"},{"key":"13966_CR9","doi-asserted-by":"publisher","unstructured":"Buenz EJ, S D, Bauer BA, Elkin PL, Riddle JM, Motley TJ (2004) Techniques: bioprospecting historical herbal texts by hunting for new leads in old tomes. Trends Pharmacol Sci 9:5. https:\/\/doi.org\/10.1016\/j.tips.2004.07.003","DOI":"10.1016\/j.tips.2004.07.003"},{"key":"13966_CR10","doi-asserted-by":"publisher","first-page":"6183","DOI":"10.1021\/acs.jcim.3c01153","volume":"33","author":"DA Case","year":"2023","unstructured":"Case DA (2023) Amber tools. J Chem Inf Model 33:6183\u20136191. https:\/\/doi.org\/10.1021\/acs.jcim.3c01153","journal-title":"J Chem Inf Model"},{"issue":"D1","key":"13966_CR11","doi-asserted-by":"publisher","first-page":"D634","DOI":"10.1093\/nar\/gkae1063","volume":"53","author":"V Chandrasekhar","year":"2024","unstructured":"Chandrasekhar V, Rajan K, Kanakam SRS, Sharma N, Weissenborn V, Schaub J, Steinbeck C (2024) COCONUT 2.0: a comprehensive overhaul and curation of the collection of open natural products database. Nucleic Acids Res 53(D1):D634\u2013D643. https:\/\/doi.org\/10.1093\/nar\/gkae1063","journal-title":"Nucleic Acids Res"},{"issue":"1593","key":"13966_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fmicb.2018.01593","volume":"9","author":"BC Chen","year":"2018","unstructured":"Chen BC, Lin CX, Chen NP, Gao CX, Zhao YJ, Qian CD (2018) Phenanthrene antibiotic targets bacterial membranes and kills Staphylococcus aureus with a low propensity for resistance development. Front Microbiol 9(1593):1\u20139. https:\/\/doi.org\/10.3389\/fmicb.2018.01593","journal-title":"Front Microbiol"},{"issue":"9","key":"13966_CR13","doi-asserted-by":"publisher","first-page":"5736","DOI":"10.3390\/md13095736","volume":"13","author":"A Cutignano","year":"2015","unstructured":"Cutignano A, Nuzzo G, Ianora A, Luongo E, Romano G, Gallo C, Sansone C, Aprea S, Mancini F, D\u2019Oro U, Fontana A (2015) Development and application of a novel SPE-method for bioassay-guided fractionation of marine extracts. Mar Drugs 13(9):5736\u20135749. https:\/\/doi.org\/10.3390\/md13095736","journal-title":"Mar Drugs"},{"issue":"12","key":"13966_CR14","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","volume":"98","author":"T Darden","year":"1993","unstructured":"Darden T, York D, Pedersen L (1993) Particle mesh Ewald - an N.Log(N) method for Ewald sums in large systems. J Chem Physics 98(12):10089\u201310092. https:\/\/doi.org\/10.1063\/1.464397","journal-title":"J Chem Physics"},{"key":"13966_CR15","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.micres.2015.10.009","volume":"182","author":"VB Deepika","year":"2016","unstructured":"Deepika VB, Murali TS, Satyamoorthy K (2016) Modulation of genetic clusters for synthesis of bioactive molecules in fungal endophytes: a review. Microbiol Res 182:125\u2013140. https:\/\/doi.org\/10.1016\/j.micres.2015.10.009","journal-title":"Microbiol Res"},{"key":"13966_CR16","doi-asserted-by":"publisher","DOI":"10.3390\/jof8020164","author":"SK Deshmukh","year":"2022","unstructured":"Deshmukh SK, Dufosse L, Chhipa H, Saxena S, Mahajan GB, Gupta MK (2022) Fungal endophytes: a potential source of antibacterial compounds. J Fungi (Basel). https:\/\/doi.org\/10.3390\/jof8020164","journal-title":"J Fungi (Basel)"},{"issue":"4","key":"13966_CR17","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/s41592-019-0344-8","volume":"16","author":"K Duhrkop","year":"2019","unstructured":"Duhrkop K, Fleischauer M, Ludwig M, Aksenov AA, Melnik AV, Meusel M, Dorrestein PC, Rousu J, Bocker S (2019) SIRIUS 4: a rapid tool for turning tandem mass spectra into metabolite structure information. Nat Methods 16(4):299. https:\/\/doi.org\/10.1038\/s41592-019-0344-8","journal-title":"Nat Methods"},{"issue":"4","key":"13966_CR18","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/s41587-020-0740-8","volume":"39","author":"K D\u00fchrkop","year":"2021","unstructured":"D\u00fchrkop K, Nothias LF, Fleischauer M, Reher R, Ludwig M, Hoffmann MA, Petras D, Gerwick WH, Rousu J, Dorrestein PC, B\u00f6cker S (2021) Systematic classification of unknown metabolites using high-resolution fragmentation mass spectra. Nat Biotechnol 39(4):462. https:\/\/doi.org\/10.1038\/s41587-020-0740-8","journal-title":"Nat Biotechnol"},{"issue":"41","key":"13966_CR19","doi-asserted-by":"publisher","first-page":"12580","DOI":"10.1073\/pnas.1509788112","volume":"112","author":"K D\u00fchrkop","year":"2015","unstructured":"D\u00fchrkop K, Shen HB, Meusel M, Rousu J, B\u00f6cker S (2015) Searching molecular structure databases with tandem mass spectra using CSI:FingerID. Proc Natl Acad Sci U S A 112(41):12580\u201312585. https:\/\/doi.org\/10.1073\/pnas.1509788112","journal-title":"Proc Natl Acad Sci U S A"},{"key":"13966_CR20","doi-asserted-by":"crossref","unstructured":"Eberhardt J, Santos-Martins D, Tillack AF, Forli S, Olson AJ (2021) AutoDock Vina 1.2.0: new docking methods, expanded force field, and Python bindings. J Chem Inf Model 61(8):3891\u20133901","DOI":"10.1021\/acs.jcim.1c00203"},{"key":"13966_CR21","doi-asserted-by":"publisher","unstructured":"Fanele A, Ndlovu SI (2023) Endophytic fungal species and exhibit antimicrobial activity against gram-positive and gram-negative multi-drug resistant clinical bacterial isolates. Bmc Complement Med Ther 23(1), ARTN 323. https:\/\/doi.org\/10.1186\/s12906-023-04157-8","DOI":"10.1186\/s12906-023-04157-8"},{"issue":"10","key":"13966_CR22","doi-asserted-by":"publisher","first-page":"786","DOI":"10.3390\/jof7100786","volume":"7","author":"MM Gakuubi","year":"2021","unstructured":"Gakuubi MM, Munusamy M, Liang ZX, Ng SB (2021) Fungal endophytes: a promising frontier for discovery of novel bioactive compounds. Journal of Fungi 7(10):786. https:\/\/doi.org\/10.3390\/jof7100786","journal-title":"Journal of Fungi"},{"key":"13966_CR23","doi-asserted-by":"publisher","unstructured":"Gonz\u00e1lez-Men\u00e9ndez V, Crespo G, Toro C, Mart\u00edn J, de Pedro N, Tormo JR, Genilloud O (2019) Extending the metabolite diversity of the endophyte. Metabolites, 9(10), ARTN 197. https:\/\/doi.org\/10.3390\/metabo9100197","DOI":"10.3390\/metabo9100197"},{"issue":"3","key":"13966_CR24","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1128\/Mmbr.00050-14","volume":"79","author":"PR Hardoim","year":"2015","unstructured":"Hardoim PR, van Overbeek LS, Berg G, Pirttil\u00e4 AM, Compant S, Campisano A, D\u00f6ring M, Sessitsch A (2015) The hidden world within plants: ecological and evolutionary considerations for defining functioning of microbial endophytes. Microbiol Mol Biol Rev 79(3):293\u2013320. https:\/\/doi.org\/10.1128\/Mmbr.00050-14","journal-title":"Microbiol Mol Biol Rev"},{"key":"13966_CR25","doi-asserted-by":"publisher","unstructured":"Horai H, Arita M, Kanaya S, Nihei Y, Ikeda T, Suwa K, Ojima Y, Tanaka K, Tanaka S, Aoshima K, Oda Y, Kakazu Y, Kusano M, Tohge T, Matsuda F, Sawada Y, Hirai MY, Nakanishi H, Ikeda K, \u2026, Nishioka T (2010) MassBank: a public repository for sharing mass spectral data for life sciences. J Mass Spectrom 45(7):703\u2013714. https:\/\/doi.org\/10.1002\/jms.1777","DOI":"10.1002\/jms.1777"},{"key":"13966_CR26","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1855-z","author":"K Jarolim","year":"2016","unstructured":"Jarolim K, Del Favero G, Ellmer D et al (2016) Dual effectiveness of Alternaria but not Fusarium mycotoxins against human topoisomerase II and bacterial gyrase. Arch Toxicol. https:\/\/doi.org\/10.1007\/s00204-016-1855-z","journal-title":"Arch Toxicol"},{"issue":"3","key":"13966_CR27","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1111\/lam.13414","volume":"72","author":"AMA Khalil","year":"2021","unstructured":"Khalil AMA, Abdelaziz AM, Khaleil MM, Hashem AH (2021) Fungal endophytes from leaves of growing in semi-arid environment as a promising source for bioactive compounds. Lett Appl Microbiol 72(3):263\u2013274. https:\/\/doi.org\/10.1111\/lam.13414","journal-title":"Lett Appl Microbiol"},{"issue":"32","key":"13966_CR28","doi-asserted-by":"publisher","first-page":"17837","DOI":"10.1039\/c8ra00820e","volume":"8","author":"GS Kiran","year":"2018","unstructured":"Kiran GS, Priyadharsini S, Sajayan A, Ravindran A, Selvin J (2018) An antibiotic agent pyrrolo[1,2-]pyrazine-1,4-dione, hexahydro isolated from a marine bacteria MSI45 effectively controls multi-drug resistant. RSC Adv 8(32):17837\u201317846. https:\/\/doi.org\/10.1039\/c8ra00820e","journal-title":"RSC Adv"},{"issue":"50","key":"13966_CR29","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1146\/annurev-genet-120215-035203","volume":"50","author":"J Macheleidt","year":"2016","unstructured":"Macheleidt J, Mattern DJ, Fischer J, Netzker T, Weber J, Schroeckh V, Valiante V, Brakhage AA (2016) Regulation and role of fungal secondary metabolites. Annu Rev Genet 50(50):371\u2013392. https:\/\/doi.org\/10.1146\/annurev-genet-120215-035203","journal-title":"Annu Rev Genet"},{"issue":"1","key":"13966_CR30","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ijid.2003.03.002","volume":"8","author":"S Magaldi","year":"2004","unstructured":"Magaldi S, Mata-Essayag S, de Capriles CH, Perez C, Colella MT, Olaizola C, Ontiveros Y (2004) Well diffusion for antifungal susceptibility testing. Int J Infect Dis 8(1):39\u201345. https:\/\/doi.org\/10.1016\/j.ijid.2003.03.002","journal-title":"Int J Infect Dis"},{"issue":"8","key":"13966_CR31","doi-asserted-by":"publisher","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","volume":"11","author":"JA Maier","year":"2015","unstructured":"Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C (2015) ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput 11(8):3696\u20133713. https:\/\/doi.org\/10.1021\/acs.jctc.5b00255","journal-title":"J Chem Theory Comput"},{"key":"13966_CR32","doi-asserted-by":"publisher","unstructured":"Makhwitine JP, Kumalo HM, Ndlovu SI, Mkhwanazi NP (2023) Epigenetic induction of secondary metabolites production in endophytic fungi and GC-MS analysis of crude metabolites with anti-HIV-1 activity. Microorganisms 11(6), ARTN 1404. https:\/\/doi.org\/10.3390\/microorganisms11061404","DOI":"10.3390\/microorganisms11061404"},{"issue":"1","key":"13966_CR33","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3390\/microbiolres13010007","volume":"13","author":"TS Maliehe","year":"2022","unstructured":"Maliehe TS, Mbambo M, Nqotheni MI, Senzo NS, Shandu JSE (2022) Antibacterial effect and mode of action of secondary metabolites from fungal endophyte associated with mill. Microbiology Research 13(1):90\u2013101. https:\/\/doi.org\/10.3390\/microbiolres13010007","journal-title":"Microbiology Research"},{"key":"13966_CR34","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens10101310","author":"G Mancuso","year":"2021","unstructured":"Mancuso G, Midiri A, Gerace E, Biondo C (2021) Bacterial antibiotic resistance: the most critical pathogens. Pathogens. https:\/\/doi.org\/10.3390\/pathogens10101310","journal-title":"Pathogens"},{"key":"13966_CR35","doi-asserted-by":"publisher","unstructured":"Miethke M, Pieroni M, Weber T, Br\u00f6nstrup M, Hammann P, Halby L, Arimondo PB, Glaser P, Aigle B, Bode HB, Moreira R, Li YN, Luzhetskyy A, Medema MH, Pernodet JL, Stadler M, Tormo JR, Genilloud O, Truman AW,\u2026Muller R (2021) Towards the sustainable discovery and development of new antibiotics. Nat Rev Chem 5(10):726\u2013749. https:\/\/doi.org\/10.1038\/s41570-021-00313-1","DOI":"10.1038\/s41570-021-00313-1"},{"issue":"9","key":"13966_CR36","doi-asserted-by":"publisher","first-page":"3314","DOI":"10.1021\/ct300418h","volume":"8","author":"BR Miller","year":"2012","unstructured":"Miller BR, McGee TD, Swails JM, Homeyer N, Gohlke H, Roitberg AE (2012) An efficient program for end-state free energy calculations. J Chem Theory Comput 8(9):3314\u20133321. https:\/\/doi.org\/10.1021\/ct300418h","journal-title":"J Chem Theory Comput"},{"key":"13966_CR37","doi-asserted-by":"publisher","unstructured":"Mohimani H, Gurevich A, Shlemov A, Mikheenko A, Korobeynikov A, Cao L, Shcherbin E, Nothias LF, Dorrestein PC, Pevzner PA (2018) Dereplication of microbial metabolites through database search of mass spectra. Nat Commun 9, ARTN 4035. https:\/\/doi.org\/10.1038\/s41467-018-06082-8","DOI":"10.1038\/s41467-018-06082-8"},{"issue":"1","key":"13966_CR38","doi-asserted-by":"publisher","first-page":"22746","DOI":"10.1038\/s41598-025-08091-2","volume":"15","author":"N Moloi","year":"2025","unstructured":"Moloi N, Khumalo MC, Nxumalo WP, Mtambo SE, Mkhwanazi NP, Ndlovu SI (2025) Combining an OSMAC approach and untargeted metabolomics to profile compounds exhibiting anti-HIV-1 activities in an endophytic fungus, P03MB2. Scientific Reports 15(1):22746. https:\/\/doi.org\/10.1038\/s41598-025-08091-2","journal-title":"Scientific Reports"},{"key":"13966_CR39","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00039","volume":"7","author":"MF Moradali","year":"2017","unstructured":"Moradali MF, Ghods S, Rehm BHA (2017) Pseudomonas aeruginosa lifestyle: a paradigm for adaptation, survival, and persistence. Front Cell Infect Microbiol 7:ARTN 39. https:\/\/doi.org\/10.3389\/fcimb.2017.00039","journal-title":"Front Cell Infect Microbiol"},{"issue":"16","key":"13966_CR40","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","volume":"30","author":"GM Morris","year":"2009","unstructured":"Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785\u20132791. https:\/\/doi.org\/10.1002\/jcc.21256","journal-title":"J Comput Chem"},{"key":"13966_CR41","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/250693","author":"DN Nair","year":"2014","unstructured":"Nair DN, Padmavathy S (2014) Impact of endophytic microorganisms on plants, environment and humans. Sci World J. https:\/\/doi.org\/10.1155\/2014\/250693","journal-title":"Sci World J"},{"issue":"4","key":"13966_CR42","doi-asserted-by":"publisher","first-page":"616","DOI":"10.3390\/microorganisms8040616","volume":"8","author":"CT Nguyen","year":"2020","unstructured":"Nguyen CT, Dhakal D, Pham VT, Nguyen HT, Sohng JK (2020) Recent advances in strategies for activation and discovery\/characterization of cryptic biosynthetic gene clusters in. Microorganisms 8(4):616. https:\/\/doi.org\/10.3390\/microorganisms8040616","journal-title":"Microorganisms"},{"key":"13966_CR43","doi-asserted-by":"publisher","unstructured":"Nothias LF, Petras D, Schmid R, D\u00fchrkop K, Rainer J, Sarvepalli A, Protsyuk I, Ernst M, Tsugawa H, Fleischauer M, Aicheler F, Aksenov AA, Alka O, Allard PM, Barsch A, Cachet X, Caraballo-Rodriguez AM, Da Silva RR, Dang T, \u2026, Dorrestein PC (2020) Feature-based molecular networking in the GNPS analysis environment. Nat Methods 17(9):905-+. https:\/\/doi.org\/10.1038\/s41592-020-0933-6","DOI":"10.1038\/s41592-020-0933-6"},{"issue":"42","key":"13966_CR44","doi-asserted-by":"publisher","first-page":"7108","DOI":"10.5897\/AJB09.1662","volume":"9","author":"UU Nwodo","year":"2010","unstructured":"Nwodo UU, Ngene AA, Iroegbu CU, Obiiyeke GC (2010) Effects of fractionation on antibacterial activity of crude extracts of Tamarindus indica. African Journal of Biotechnology 9(42):7108\u20137113. https:\/\/doi.org\/10.5897\/AJB09.1662","journal-title":"African Journal of Biotechnology"},{"key":"13966_CR45","doi-asserted-by":"publisher","first-page":"1077159","DOI":"10.3389\/fgene.2022.1077159","volume":"13","author":"B Nzimande","year":"2022","unstructured":"Nzimande B, Kumalo HM, Ndlovu SI, Mkhwanazi NP (2022) Secondary metabolites produced by endophytic fungi, Alternaria alternata as potential inhibitors of the human immunodeficiency virus. Frontiers in Genetics 13:1077159. https:\/\/doi.org\/10.3389\/fgene.2022.1077159","journal-title":"Frontiers in Genetics"},{"key":"13966_CR46","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-3-33","volume":"3","author":"NM O'Boyle","year":"2011","unstructured":"O\u2019Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) Open Babel: an open chemical toolbox. J Cheminform 3:33. https:\/\/doi.org\/10.1186\/1758-2946-3-33","journal-title":"J Cheminform"},{"issue":"2","key":"13966_CR47","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s12551-016-0247-1","volume":"9","author":"NS Pagadala","year":"2017","unstructured":"Pagadala NS, Syed K, Tuszynski J (2017) Software for molecular docking: a review. Biophys Rev 9(2):91\u2013102. https:\/\/doi.org\/10.1007\/s12551-016-0247-1","journal-title":"Biophys Rev"},{"key":"13966_CR48","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.815008","author":"LC Pillay","year":"2022","unstructured":"Pillay LC, Nekati L, Makhwitine PJ, Ndlovu SI (2022) Epigenetic activation of silent biosynthetic gene clusters in endophytic fungi using small molecular modifiers. Front Microbiol. https:\/\/doi.org\/10.3389\/fmicb.2022.815008","journal-title":"Front Microbiol"},{"issue":"2","key":"13966_CR49","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1111\/j.1469-8137.2009.02773.x","volume":"182","author":"RJ Rodriguez","year":"2009","unstructured":"Rodriguez RJ, White JF, Arnold AE, Redman RS (2009) Fungal endophytes: diversity and functional roles. New Phytol 182(2):314\u2013330. https:\/\/doi.org\/10.1111\/j.1469-8137.2009.02773.x","journal-title":"New Phytol"},{"issue":"7","key":"13966_CR50","doi-asserted-by":"publisher","first-page":"3084","DOI":"10.1021\/ct400341p","volume":"9","author":"DR Roe","year":"2013","unstructured":"Roe DR, Cheatham TE (2013) PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput 9(7):3084\u20133095. https:\/\/doi.org\/10.1021\/ct400341p","journal-title":"J Chem Theory Comput"},{"key":"13966_CR51","doi-asserted-by":"publisher","DOI":"10.3390\/md16070244","author":"S Romano","year":"2018","unstructured":"Romano S, Jackson SA, Patry S, Dobson ADW (2018) Extending the \u201cone strain many compounds\u201d (OSMAC) principle to marine microorganisms. Mar Drugs. https:\/\/doi.org\/10.3390\/md16070244","journal-title":"Mar Drugs"},{"issue":"3","key":"13966_CR52","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","volume":"23","author":"JP Ryckaert","year":"1977","unstructured":"Ryckaert JP, Ciccotti G, Berendsen HJ (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23(3):327\u2013341. https:\/\/doi.org\/10.1016\/0021-9991(77)90098-5","journal-title":"J Comput Phys"},{"issue":"9","key":"13966_CR53","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1039\/b821578b","volume":"7","author":"K Scherlach","year":"2009","unstructured":"Scherlach K, Hertweck C (2009) Triggering cryptic natural product biosynthesis in microorganisms. Org Biomol Chem 7(9):1753\u20131760. https:\/\/doi.org\/10.1039\/b821578b","journal-title":"Org Biomol Chem"},{"key":"13966_CR54","doi-asserted-by":"publisher","unstructured":"Schmid R, Heuckeroth S, Korf A, Smirnov A, Myers O, Dyrlund TS, Bushuiev R, Murray KJ, Hoffmann N, Lu MS, Sarvepalli A, Zhang Z, Fleischauer M, D\u00fcrkop K, Wesner M, Hoogstra SJ, Rudt E, Mokshyna O, Brungs C, \u2026, Pluskal T (2023) Integrative analysis of multimodal mass spectrometry data in MZmine 3. Nat Biotechnol 41(4):447\u2013449. https:\/\/doi.org\/10.1038\/s41587-023-01690-2","DOI":"10.1038\/s41587-023-01690-2"},{"key":"13966_CR55","unstructured":"Schr\u00f6dinger LADW (2024) PyMol. https:\/\/www.pymol.org\/. Accessed 15 Aug 2025"},{"key":"13966_CR56","doi-asserted-by":"publisher","unstructured":"Shah AKP, Walter A, Ottosson F, Russo F, Navarro-Diaz M, Boldt J, Kalinski JCJ, Kontou EE, Elofson J, Polyzois A, Gonz\u00edlez-Mar\u00edn C, Farrell S, Aggerbeck MR, Pruksatrakul T, Chan NT, Wang YS, P\u00f6chhacker M, Brungs C, C\u00e1mara B, \u2026, Petras D (2025) Statistical analysis of feature-based molecular networking results from non-targeted metabolomics data. Nat Protoc 20(1). https:\/\/doi.org\/10.1038\/s41596-024-01046-3","DOI":"10.1038\/s41596-024-01046-3"},{"issue":"11","key":"13966_CR57","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498\u20132504. https:\/\/doi.org\/10.1101\/gr.1239303","journal-title":"Genome Res"},{"issue":"3","key":"13966_CR58","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1007\/s12010-021-03702-w","volume":"194","author":"MH Sharaf","year":"2022","unstructured":"Sharaf MH, Abdelaziz AM, Kalaba MH, Radwan AA, Hashem AH (2022) Antimicrobial, antioxidant, cytotoxic activities and phytochemical analysis of fungal endophytes isolated from Ocimum basilicum. Appl Biochem Biotechnol 194(3):1271\u20131289. https:\/\/doi.org\/10.1007\/s12010-021-03702-w","journal-title":"Appl Biochem Biotechnol"},{"key":"13966_CR59","doi-asserted-by":"publisher","unstructured":"Stoszko M, Al-Hatmi AMS, Skriba A, Roling M, Ne E, Crespo R, Mueller YM, Najafzadeh MJ, Kang J, Ptackova R, LeMasters E, Biswas P, Bertoldi A, Kan TW, de Crignis E, Sulc M, Lebbink JHG, Rokx C, Verbon A, \u2026, Mahmoudi T (2020) Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency. Sci Adv 6(33):eaba6617. https:\/\/doi.org\/10.1126\/sciadv.aba6617","DOI":"10.1126\/sciadv.aba6617"},{"key":"13966_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2020.112338","volume":"174","author":"RMK Toghueo","year":"2020","unstructured":"Toghueo RMK, Sahal D, Boyom FF (2020) Recent advances in inducing endophytic fungal specialized metabolites using small molecule elicitors including epigenetic modifiers. Phytochemistry 174:112338. https:\/\/doi.org\/10.1016\/j.phytochem.2020.112338","journal-title":"Phytochemistry"},{"issue":"3","key":"13966_CR61","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1128\/CMR.00134-14","volume":"28","author":"SY Tong","year":"2015","unstructured":"Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG Jr (2015) Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 28(3):603\u2013661. https:\/\/doi.org\/10.1128\/CMR.00134-14","journal-title":"Clin Microbiol Rev"},{"issue":"2","key":"13966_CR62","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","volume":"31","author":"O Trott","year":"2010","unstructured":"Trott O, Olson AJ (2010) Software news and update AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455\u2013461. https:\/\/doi.org\/10.1002\/jcc.21334","journal-title":"J Comput Chem"},{"issue":"3","key":"13966_CR63","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/j.jep.2008.05.038","volume":"119","author":"SF van Vuuren","year":"2008","unstructured":"van Vuuren SF (2008) Antimicrobial activity of South African medicinal plants. J Ethnopharmacol 119(3):462\u2013472. https:\/\/doi.org\/10.1016\/j.jep.2008.05.038","journal-title":"J Ethnopharmacol"},{"key":"13966_CR64","doi-asserted-by":"publisher","unstructured":"Vo TH, Bui QH, Nguyen HH, Pham HT (2022) Antimicrobial resistance patterns of Pseudomonas aeruginosa in a Vietnamese tertiary care Hospital. Int J Trop Dis 5:058. https:\/\/doi.org\/10.23937\/2643-461X\/1710058","DOI":"10.23937\/2643-461X\/1710058"},{"issue":"9","key":"13966_CR65","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","volume":"25","author":"JM Wang","year":"2004","unstructured":"Wang JM, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. Journal of Computational Chemistry 25(9):1157\u20131174. https:\/\/doi.org\/10.1002\/jcc.20035","journal-title":"Journal of Computational Chemistry"},{"key":"13966_CR66","doi-asserted-by":"publisher","unstructured":"Wang MX, Carver JJ, Phelan VV, Sanchez LM, Garg N, Peng Y, Nguyen DD, Watrous J, Kapono CA, Luzzatto-Knaan T, Porto C, Bouslimani A, Melnik AV, Meehan MJ, Liu WT, Criisemann M, Boudreau PD, Esquenazi E, Sandoval-Calder\u00f3n M,\u2026Bandeira N (2016) Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat Biotechnol 34(8):828\u2013837. https:\/\/doi.org\/10.1038\/nbt.3597","DOI":"10.1038\/nbt.3597"},{"issue":"20","key":"13966_CR67","doi-asserted-by":"publisher","first-page":"5912","DOI":"10.1021\/jm050362n","volume":"49","author":"GL Warren","year":"2006","unstructured":"Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS (2006) A critical assessment of docking programs and scoring functions. J Med Chem 49(20):5912\u20135931. https:\/\/doi.org\/10.1021\/jm050362n","journal-title":"J Med Chem"},{"issue":"10","key":"13966_CR68","doi-asserted-by":"publisher","first-page":"3845","DOI":"10.1039\/c3sc51785c","volume":"4","author":"Z Wasil","year":"2013","unstructured":"Wasil Z, Pahirulzaman KAK, Butts C, Simpson TJ, Lazarus CM, Cox RJ (2013) One pathway, many compounds: heterologous expression of a fungal biosynthetic pathway reveals its intrinsic potential for diversity. Chem Sci 4(10):3845\u20133856. https:\/\/doi.org\/10.1039\/c3sc51785c","journal-title":"Chem Sci"},{"key":"13966_CR69","unstructured":"WHO (2019) Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline. https:\/\/www.who.int\/antimicrobial-resistance\/en\/. Accessed 12 Aug 2025"},{"key":"13966_CR70","doi-asserted-by":"publisher","unstructured":"WHO (2022) Antimicrobial resistance collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis (vol 399, pg 629, 2022). Lancet 400(10358):1102\u20131102. https:\/\/doi.org\/10.1016\/S0140-6736(21)02653-2","DOI":"10.1016\/S0140-6736(21)02653-2"},{"issue":"4","key":"13966_CR71","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics14040334","volume":"14","author":"Z Zhang","year":"2025","unstructured":"Zhang Z, Cao M, Shang Z, Xu J, Chen X, Zhu Z, Wang W, Wei X, Zhou X, Bai Y, Zhang J (2025) Research progress on the antibacterial activity of natural flavonoids. Antibiotics 14(4):334. https:\/\/doi.org\/10.3390\/antibiotics14040334","journal-title":"Antibiotics"},{"issue":"32","key":"13966_CR72","doi-asserted-by":"publisher","first-page":"6791","DOI":"10.1021\/acs.jpca.3c04215","volume":"127","author":"CY Zhao","year":"2023","unstructured":"Zhao CY, Wu RK, Zhang SQ, Hong X (2023) Benchmark study of density functional theory methods in geometry optimization of transition metal-dinitrogen complexes. J Phys Chem A 127(32):6791\u20136803. https:\/\/doi.org\/10.1021\/acs.jpca.3c04215","journal-title":"J Phys Chem A"}],"container-title":["Applied Microbiology and Biotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00253-026-13966-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00253-026-13966-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00253-026-13966-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:37:25Z","timestamp":1792453045000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00253-026-13966-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["13966"],"URL":"https:\/\/doi.org\/10.1007\/s00253-026-13966-z","relation":{},"ISSN":["1432-0614"],"issn-type":[{"value":"1432-0614","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]},"assertion":[{"value":"21 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable since this study does not contain any experiment on humans or animals.","order":1,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors read the final manuscript and give permission to publish.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"313"}}