{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T11:04:57Z","timestamp":1777633497420,"version":"3.51.4"},"reference-count":134,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T00:00:00Z","timestamp":1690588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"national funds through FCT\/MCTES (PIDDAC)"},{"name":"FEDER funds through COMPETE2020\u2014Programa Operacional Competitividade e Internacionaliza\u00e7\u00e3o (POCI)"},{"name":"national funds (PIDDAC) through FCT\/MCTES"},{"name":"FCT grant","award":["2020.04773.BD"],"award-info":[{"award-number":["2020.04773.BD"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Antibiotics are a staple in current medicine for the therapy of infectious diseases. However, their extensive use and misuse, combined with the high adaptability of bacteria, has dangerously increased the incidence of multi-drug-resistant (MDR) bacteria. This makes the treatment of infections challenging, especially when MDR bacteria form biofilms. The most recent antibiotics entering the market have very similar modes of action to the existing ones, so bacteria rapidly catch up to those as well. As such, it is very important to adopt effective measures to avoid the development of antibiotic resistance by pathogenic bacteria, but also to perform bioprospecting of new molecules from diverse sources to expand the arsenal of drugs that are available to fight these infectious bacteria. Filamentous fungi have a large and vastly unexplored secondary metabolome and are rich in bioactive molecules that can be potential novel antimicrobial drugs. Their production can be challenging, as the associated biosynthetic pathways may not be active under standard culture conditions. New techniques involving metabolic and genetic engineering can help boost antibiotic production. This study aims to review the bioprospection of fungi to produce new drugs to face the growing problem of MDR bacteria and biofilm-associated infections.<\/jats:p>","DOI":"10.3390\/antibiotics12081250","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T01:28:46Z","timestamp":1690766926000},"page":"1250","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Beyond Penicillin: The Potential of Filamentous Fungi for Drug Discovery in the Age of Antibiotic Resistance"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3202-7223","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Correia","sequence":"first","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, Department of Chemical Engineering, University of Porto, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6929-6805","authenticated-orcid":false,"given":"Anabela","family":"Borges","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, Department of Chemical Engineering, University of Porto, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3355-4398","authenticated-orcid":false,"given":"Manuel","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"LEPABE\u2014Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, Department of Chemical Engineering, University of Porto, 4200-465 Porto, Portugal"},{"name":"ALiCE\u2014Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4893-1985","authenticated-orcid":false,"given":"L\u00facia","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"CEB\u2014Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"LABBELS\u2014Associate Laboratory in Biotechnology, Bioengineering and Microelectromechanical Systems, 4710-057 Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,29]]},"reference":[{"key":"ref_1","first-page":"56","article-title":"The treasure called antibiotics","volume":"14","author":"Adedeji","year":"2016","journal-title":"Ann. Ib. Postgrad. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2147\/IDR.S287792","article-title":"Encouraging the development of new antibiotics: Are financial incentives the right way forward? A systematic review and case study","volume":"14","author":"Dutescu","year":"2021","journal-title":"Infect. Drug Resist."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1016\/j.jiph.2021.10.020","article-title":"Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects","volume":"14","author":"Uddin","year":"2021","journal-title":"J. Infect. Public Health"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ron\u010devi\u0107, T., Puizina, J., and Tossi, A. (2019). Antimicrobial Peptides as Anti-Infective Agents in Pre-Post-Antibiotic Era?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225713"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Borges, A., Abreu, A.C., Dias, C., Saavedra, M.J., Borges, F., and Sim\u00f5es, M. (2016). New perspectives on the use of phytochemicals as an emergent strategy to control bacterial infections including biofilms. Molecules, 21.","DOI":"10.3390\/molecules21070877"},{"key":"ref_6","first-page":"E1","article-title":"Fluoroquinolones: Then and now","volume":"32","author":"Byron","year":"2010","journal-title":"Compend. Contin. Educ. Vet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"181","DOI":"10.2174\/1568005014606099","article-title":"The discovery of linezolid, the first oxazolidinone antibacterial agent","volume":"1","author":"Ford","year":"2001","journal-title":"Curr. Drug Targets-Infect. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.1749-6632.2011.06219.x","article-title":"Are pleuromutilin antibiotics finally fit for human use?","volume":"1241","author":"Novak","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1039\/C8NP00031J","article-title":"Nonribosomal antibacterial peptides that target multidrug-resistant bacteria","volume":"36","author":"Liu","year":"2019","journal-title":"Nat. Prod. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"129477","DOI":"10.1016\/j.jhazmat.2022.129477","article-title":"Evaluation of culturable \u2018last-resort\u2019 antibiotic resistant pathogens in hospital wastewater and implications on the risks of nosocomial antimicrobial resistance prevalence","volume":"438","author":"Li","year":"2022","journal-title":"J. Hazard. Mater."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Balice, G., Passino, C., Bongiorni, M.G., Segreti, L., Russo, A., Lastella, M., Luci, G., Falcone, M., and Di Paolo, A. (2022). Daptomycin population pharmacokinetics in patients affected by severe gram-positive infections: An update. Antibiotics, 11.","DOI":"10.3390\/antibiotics11070914"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102767","DOI":"10.1016\/j.copbio.2022.102767","article-title":"Beyond vancomycin: Recent advances in the modification, reengineering, production and discovery of improved glycopeptide antibiotics to tackle multidrug-resistant bacteria","volume":"77","author":"Hansen","year":"2022","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_13","unstructured":"O\u2019Neill, J. (2014). Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations, Review on Antimicrobial Resistance."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"De Kraker, M.E.A., Stewardson, A.J., and Harbarth, S. (2016). Will 10 Million People Die a Year due to Antimicrobial Resistance by 2050?. PLoS Med., 13.","DOI":"10.1371\/journal.pmed.1002184"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3109\/1040841X.2013.804031","article-title":"Horizontal gene transfer in human pathogens","volume":"41","author":"Juhas","year":"2015","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12941-015-0108-y","article-title":"The spread of bla OXA-48 and bla OXA-244 carbapenemase genes among Klebsiella pneumoniae, Proteus mirabilis and Enterobacter spp. isolated in Moscow, Russia","volume":"14","author":"Fursova","year":"2015","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Serweci\u0144ska, L. (2020). Antimicrobials and antibiotic-resistant bacteria: A risk to the environment and to public health. Water, 12.","DOI":"10.3390\/w12123313"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"118136","DOI":"10.1016\/j.envpol.2021.118136","article-title":"Emergence of colistin resistance genes (mcr-1) in Escherichia coli among widely distributed wild ungulates","volume":"291","author":"Torres","year":"2021","journal-title":"Environ. Pollut."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ibiod.2013.06.011","article-title":"The effects of ferulic and salicylic acids on Bacillus cereus and Pseudomonas fluorescens single- and dual-species biofilms","volume":"86","author":"Lemos","year":"2014","journal-title":"Int. Biodeterior. Biodegrad."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13756-019-0533-3","article-title":"Antibiotics versus biofilm: An emerging battleground in microbial communities","volume":"8","author":"Sharma","year":"2019","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1080\/08927014.2012.706751","article-title":"The activity of ferulic and gallic acids in biofilm prevention and control of pathogenic bacteria","volume":"28","author":"Borges","year":"2012","journal-title":"Biofouling"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1128\/AAC.38.9.2125","article-title":"Investigation of ciprofloxacin penetration into Pseudomonas aeruginosa biofilms","volume":"38","author":"Suci","year":"1994","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/485439a","article-title":"Recover the lost art of drug discovery","volume":"485","author":"Lewis","year":"2012","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fmicb.2010.00134","article-title":"A brief history of the antibiotic era: Lessons learned and challenges for the future","volume":"1","author":"Aminov","year":"2010","journal-title":"Front. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.trsl.2020.02.006","article-title":"Evaluating for-profit public benefit corporations as an additional structure for antibiotic development and commercialization","volume":"220","author":"Outterson","year":"2020","journal-title":"Transl. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113321","DOI":"10.1016\/j.jpeds.2023.01.001","article-title":"The shortage of amoxicillin: An escalating public health crisis in pediatrics faced by several western countries","volume":"257","author":"Cohen","year":"2023","journal-title":"J. Pediatr."},{"key":"ref_27","first-page":"56","article-title":"Reinvigorating Puerto Rico\u2019s pharmaceutical industry: A US security imperative","volume":"33","author":"Garcia","year":"2021","journal-title":"Cent. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"87","DOI":"10.5598\/imafungus.2011.02.01.12","article-title":"Fleming\u2019s penicillin producing strain is not Penicillium chrysogenum but P. rubens","volume":"2","author":"Houbraken","year":"2011","journal-title":"IMA Fungus"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1163\/22977953-04501006","article-title":"The development of sulfonamides (1932\u20131938) as a focal point in the history of chemotherapy","volume":"45","author":"Bickel","year":"1988","journal-title":"Gesnerus"},{"key":"ref_30","unstructured":"National Center for Biotechnology Information (2023, May 24). PubChem Compound Summary for CID 66895, Prontosil, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Prontosil."},{"key":"ref_31","unstructured":"National Center for Biotechnology Information (2023, May 24). PubChem Compound Summary for CID 8774, Arsphenamine, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Arsphenamine."},{"key":"ref_32","unstructured":"National Center for Biotechnology Information (2023, May 24). PubChem Compound Summary for CID 76961391, Neosalvarsan, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Neosalvarsan."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.mib.2019.10.008","article-title":"Antibiotics: Past, present and future","volume":"51","author":"Hutchings","year":"2019","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S1359-6446(04)03285-4","article-title":"Antibiotics: Where did we go wrong?","volume":"10","author":"Overbye","year":"2005","journal-title":"Drug Discov. Today"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1016\/S0924-8579(09)70544-8","article-title":"Why is community-associated MRSA spreading across the world and how will it change clinical practice?","volume":"34","author":"Bassetti","year":"2009","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1039\/C9MD00044E","article-title":"Methicillin-resistant Staphylococcus aureus (MRSA): Antibiotic-resistance and the biofilm phenotype","volume":"10","author":"Craft","year":"2019","journal-title":"MedChemComm"},{"key":"ref_37","unstructured":"Stadler, M., and Dersch, P. (2016). Exploitation of fungal biodiversity for discovery of novel antibiotics. How to Overcome the Antibiotic Crisis: Facts, Challenges, Technologies and Future Perspectives, Springer International Publishing."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nrd4510","article-title":"The re-emergence of natural products for drug discovery in the genomics era","volume":"14","author":"Harvey","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_40","unstructured":"United Nations (1992). Convention on Biological Diversity, United Nations."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"939","DOI":"10.4155\/fmc-2019-0307","article-title":"An overview of drug discovery and development","volume":"12","author":"Berdigaliyev","year":"2020","journal-title":"Future Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Romano, S., Jackson, S.A., Patry, S., and Dobson, A.D.W. (2018). Extending the \u201cone strain many compounds\u201d (OSMAC) principle to marine microorganisms. Mar. Drugs, 16.","DOI":"10.3390\/md16070244"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41579-018-0121-1","article-title":"Fungal secondary metabolism: Regulation, function and drug discovery","volume":"17","author":"Keller","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_44","unstructured":"Romero-Gonz\u00e1lez, R., and Frenich, A.G. (2017). HRMS: Fundamentals and Basic Concepts. Applications in High Resolution Mass Spectrometry, Elsevier."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1128\/MMBR.66.3.447-459.2002","article-title":"Relationship between secondary metabolism and fungal development","volume":"66","author":"Calvo","year":"2002","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kavanagh, K. (2011). Fungi: Biology and Applications, John Wiley & Sons, Inc.. [2nd ed.].","DOI":"10.1002\/9781119976950"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1111\/mmi.14277","article-title":"Bacteria-induced production of the antibacterial sesquiterpene lagopodin B in Coprinopsis cinerea","volume":"112","author":"Morinaka","year":"2019","journal-title":"Mol. Microbiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cub.2014.11.018","article-title":"Redox metabolites signal polymicrobial biofilm development via the NapA oxidative stress cascade in Aspergillus","volume":"25","author":"Zheng","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.phytochem.2017.05.015","article-title":"Antibacterial and antibiofilm activities of the metabolites isolated from the culture of the mangrove-derived endophytic fungus Eurotium chevalieri KUFA 0006","volume":"141","author":"Buttachon","year":"2017","journal-title":"Phytochemistry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/ja.2015.50","article-title":"Avellanin C, an inhibitor of quorum-sensing signaling in Staphylococcus aureus, from Hamigera ingelheimensis","volume":"68","author":"Igarashi","year":"2015","journal-title":"J. Antibiot."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S1367-5931(03)00020-6","article-title":"Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms","volume":"7","author":"Shen","year":"2003","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_52","first-page":"1637","article-title":"Advances in metabolic engineering of filamentous fungi","volume":"37","author":"Li","year":"2021","journal-title":"Sheng Wu Gong Cheng Xue Bao"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Niu, X., Thaochan, N., and Hu, Q. (2020). Diversity of Linear Non-Ribosomal Peptide in Biocontrol Fungi. J. Fungi, 6.","DOI":"10.3390\/jof6020061"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/ja.2014.129","article-title":"A new enniatin antibiotic from the endophyte Fusarium tricinctum Corda","volume":"68","author":"Zaher","year":"2015","journal-title":"J. Antibiot."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1136\/adc.2003.019695","article-title":"Fusidic acid resistance in Staphylococcus aureus","volume":"89","author":"Dobie","year":"2004","journal-title":"Arch. Dis. Child."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Frisvad, J.C. (2012). Media and growth conditions for induction of secondary metabolite production. Fungal Secondary Metabolism, Humana Press.","DOI":"10.1007\/978-1-62703-122-6_3"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"25119","DOI":"10.1039\/C9RA03678D","article-title":"Expanding the chemical diversity of an endophytic fungus Bulgaria inquinans, an ascomycete associated with mistletoe, through an OSMAC approach","volume":"9","author":"Ariantari","year":"2019","journal-title":"RSC Adv."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1021\/np070504b","article-title":"Uncovering biosynthetic potential of plant-associated fungi: Effect of culture conditions on metabolite production by Paraphaeosphaeria quadriseptata and Chaetomium chiversii","volume":"70","author":"Paranagama","year":"2007","journal-title":"J. Nat. Prod."},{"key":"ref_59","unstructured":"(2014). Bioprocess Engineering: Basic Concepts, Pearson Education Limited. [2nd ed.]."},{"key":"ref_60","unstructured":"Lima, N., and Mota, M. (2000). Biotecnologia microbiana: A produ\u00e7\u00e3o de penicilina. Biotecnologia: Fundamentos e Aplica\u00e7\u00f5es, DIFEL. [1st ed.]."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1021\/bp00031a013","article-title":"Pellet formation and fragmentation in submerged cultures of Penicillium chrysogenum and its relation to penicillin production","volume":"11","author":"Nielsen","year":"1995","journal-title":"Biotechnol. Prog."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1007\/s00253-018-8818-7","article-title":"The filamentous fungal pellet\u2014Relationship between morphology and productivity","volume":"102","author":"Veiter","year":"2018","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00253-003-1504-3","article-title":"Biotechnological advantages of laboratory-scale solid-state fermentation with fungi","volume":"64","author":"Lenz","year":"2004","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_64","first-page":"480","article-title":"Solid state and submerged fermentation for the production of bioactive substances: A comparative study","volume":"3","author":"Subramaniyam","year":"2012","journal-title":"Int. J. Sci. Nat."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1080\/07388551.2019.1577798","article-title":"Production of bioactive metabolites by submerged fermentation of the medicinal mushroom Antrodia cinnamomea: Recent advances and future development","volume":"39","author":"Zhang","year":"2019","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_66","unstructured":"Stanbury, P.F., Whitaker, A., and Hall, S.J. (2017). Principles of Fermentation Technology, Elsevier."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1080\/07388550091144177","article-title":"Growth of filamentous fungi in submerged culture: Problems and possible solutions","volume":"20","author":"Gibbs","year":"2000","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/(SICI)1097-0290(20000420)68:2<160::AID-BIT5>3.0.CO;2-P","article-title":"Effect of biomass concentration and mycelial morphology on fermentation broth rheology","volume":"68","author":"Riley","year":"2000","journal-title":"Biotechnol. Bioeng."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"265","DOI":"10.4331\/wjbc.v6.i3.265","article-title":"Effect of agitation speed on the morphology of Aspergillus niger HFD5A-1 hyphae and its pectinase production in submerged fermentation","volume":"6","author":"Ibrahim","year":"2015","journal-title":"World J. Biol. Chem."},{"key":"ref_70","first-page":"34","article-title":"Effect of agitation speed on morphological changes in Aspergillus niger hyphae during production of tannase","volume":"4","author":"Purwanto","year":"2009","journal-title":"World J. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"114","DOI":"10.7164\/antibiotics.56.114","article-title":"Coniosetin, a novel tetramic acid antibiotic from Coniochaeta ellipsoidea DSM 13856","volume":"56","author":"Segeth","year":"2003","journal-title":"J. Antibiot."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S1369-703X(02)00121-3","article-title":"Solid-state fermentation","volume":"13","author":"Pandey","year":"2003","journal-title":"Biochem. Eng. J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"124566","DOI":"10.1016\/j.biortech.2020.124566","article-title":"Recent developments on solid-state fermentation for production of microbial secondary metabolites: Challenges and solutions","volume":"323","author":"Kumar","year":"2021","journal-title":"Bioresour. Technol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"107521","DOI":"10.1016\/j.biotechadv.2020.107521","article-title":"Expanding the chemical diversity through microorganisms co-culture: Current status and outlook","volume":"40","author":"Arora","year":"2020","journal-title":"Biotechnol. Adv."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s12223-019-00725-z","article-title":"Study of in vitro interaction between Fusarium verticillioides and Streptomyces sp. using metabolomics","volume":"65","author":"Nguyen","year":"2020","journal-title":"Folia Microbiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s10600-011-0053-8","article-title":"Aspergicin, a new antibacterial alkaloid produced by mixed fermentation of two marine-derived mangrove epiphytic fungi","volume":"47","author":"Zhu","year":"2011","journal-title":"Chem. Nat. Compd."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.copbio.2017.11.012","article-title":"Use of bacterial co-cultures for the efficient production of chemicals","volume":"53","author":"Jones","year":"2018","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1039\/C8RA09067J","article-title":"Co-culture of the fungus Fusarium tricinctum with Streptomyces lividans induces production of cryptic naphthoquinone dimers","volume":"9","author":"Moussa","year":"2019","journal-title":"RSC Advances"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1021\/acs.jnatprod.7b00133","article-title":"The berkeleylactones, antibiotic macrolides from fungal coculture","volume":"80","author":"Stierle","year":"2017","journal-title":"Journal of Natural Products"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.phytol.2015.02.009","article-title":"Inducing secondary metabolite production by the soil-dwelling fungus Aspergillus terreus through bacterial co-culture","volume":"12","author":"Chen","year":"2015","journal-title":"Phytochem. Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s10529-018-2619-z","article-title":"Advances in heterologous biosynthesis of plant and fungal natural products by modular co-culture engineering","volume":"41","author":"Chen","year":"2019","journal-title":"Biotechnol. Lett."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"34953","DOI":"10.1074\/jbc.M114.599878","article-title":"Copsin, a novel peptide-based fungal antibiotic interfering with the peptidoglycan synthesis","volume":"289","author":"Essig","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Sung, A.A., Gromek, S.M., and Balunas, M.J. (2017). Upregulation and identification of antibiotic activity of a marine-derived Streptomyces sp. via co-cultures with human pathogens. Mar. Drugs, 15.","DOI":"10.3390\/md15080250"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Martinez, J.A., Delvenne, M., Henrion, L., Moreno, F., Telek, S., Dusny, C., and Delvigne, F. (2022). Controlling microbial co-culture based on substrate pulsing can lead to stability through differential fitness advantages. PLoS Comput. Biol., 18.","DOI":"10.1101\/2022.02.18.480836"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/bab.1154","article-title":"Enhanced production of Monacolin K by addition of precursors and surfactants in submerged fermentation of Monascus purpureus 9901","volume":"61","author":"Zhang","year":"2014","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5652","DOI":"10.1002\/jsfa.11218","article-title":"Promotion of monacolin K production in Monascus extractive fermentation: The variation in fungal morphology and in the expression levels of biosynthetic gene clusters","volume":"101","author":"Yang","year":"2021","journal-title":"J. Sci. Food Agric."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00449-020-02418-1","article-title":"Enhanced exopolysaccharide production in submerged fermentation of Ganoderma lucidum by Tween 80 supplementation","volume":"44","author":"Yang","year":"2021","journal-title":"Bioprocess Biosyst. Eng."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"35","DOI":"10.5958\/2322-0996.2017.00019.9","article-title":"Standardization of Nutrient Salt Solution for Improved Production of Cellulase from C. cinerea","volume":"7","author":"Maan","year":"2017","journal-title":"Biotech Today Int. J. Biol. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0007-1536(88)80062-7","article-title":"Effect of polymeric additives, especially Junlon and Hostacerin, on growth of some basidiomycetes in submerged culture","volume":"90","author":"Jones","year":"1988","journal-title":"Trans. Br. Mycol. Soc."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"9729","DOI":"10.1038\/s41598-018-28192-5","article-title":"Fungal endophytes from arid areas of Andalusia: High potential sources for antifungal and antitumoral agents","volume":"8","author":"Crespo","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.biotechadv.2015.07.004","article-title":"Endophytes as in vitro production platforms of high value plant secondary metabolites","volume":"33","author":"Venugopalan","year":"2015","journal-title":"Biotechnol. Adv."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"14221","DOI":"10.3390\/molecules190914221","article-title":"Enhanced production of botrallin and TMC-264 with in Situ macroporous resin adsorption in mycelial liquid culture of the endophytic fungus Hyalodendriella sp. Ponipodef12","volume":"19","author":"Luo","year":"2014","journal-title":"Molecules"},{"key":"ref_93","unstructured":"Gonz\u00e1lez Men\u00e9ndez, V.M. (2019). Enhancement of Chemical Diversity in Fungal Endophytes from Arid Plants of Andalusia. [Ph.D. Thesis, Universidad de Granada]."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1021\/acschembio.5b00025","article-title":"Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation","volume":"10","author":"Albright","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s13205-018-1308-x","article-title":"Engineering fungal morphology for enhanced production of hydrolytic enzymes by Aspergillus oryzae SBS50 using microparticles","volume":"8","author":"Singh","year":"2018","journal-title":"3 Biotech"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5832496","DOI":"10.1155\/2019\/5832496","article-title":"Application of aluminum oxide nanoparticles in Aspergillus terreus cultivations: Evaluating the effects on lovastatin production and fungal morphology","volume":"2019","author":"Boruta","year":"2019","journal-title":"BioMed Res. Int."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/elsc.201300055","article-title":"Adding talc microparticles to Aspergillus terreus ATCC 20542 preculture decreases fungal pellet size and improves lovastatin production","volume":"14","author":"Gonciarz","year":"2014","journal-title":"Eng. Life Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00253-010-2551-1","article-title":"Bikaverin production and applications","volume":"87","author":"Avalos","year":"2010","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/ja.2010.78","article-title":"Carbon source regulation of antibiotic production","volume":"63","author":"Forero","year":"2010","journal-title":"J. Antibiot."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1128\/JB.182.9.2355-2362.2000","article-title":"Molecular control of expression of penicillin biosynthesis genes in fungi: Regulatory proteins interact with a bidirectional promoter region","volume":"182","year":"2000","journal-title":"J. Bacteriol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.1002\/j.1460-2075.1993.tb06072.x","article-title":"pH regulation is a major determinant in expression of a fungal penicillin biosynthetic gene","volume":"12","author":"Espeso","year":"1993","journal-title":"EMBO J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.3390\/md10122912","article-title":"Isolation, Structure Elucidation and Total Synthesis of Lajollamide A from the Marine Fungus Asteromyces cruciatus","volume":"10","author":"Gulder","year":"2012","journal-title":"Mar. Drugs"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"4992","DOI":"10.1021\/acs.biochem.7b00697","article-title":"Structural insights into the mode of action of the peptide antibiotic copsin","volume":"56","author":"Franzoi","year":"2017","journal-title":"Biochemistry"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.1021\/ja00032a035","article-title":"Trichogin A IV, an 11-residue lipopeptaibol from Trichoderma longibrachiatum","volume":"114","author":"Rebuffat","year":"1992","journal-title":"J. Am. Chem. Soc."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/psc.1135","article-title":"Trichogin GA IV: An antibacterial and protease-resistant peptide TRICHOGIN GA IV","volume":"15","year":"2009","journal-title":"J. Pept. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.fitote.2018.10.008","article-title":"Induction of new metabolites from sponge-associated fungus Aspergillus carneus by OSMAC approach","volume":"131","author":"Ebrahim","year":"2018","journal-title":"Fitoterapia"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"821","DOI":"10.7164\/antibiotics.55.821","article-title":"Oxasetin, a new antibacterial polyketide produced by fungus Vaginatispora aquatica, HK1821","volume":"55","author":"He","year":"2002","journal-title":"J. Antibiot."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Banks, A.M., Song, L., Challis, G.L., Bailey, A.M., and Foster, G.D. (2020). Bovistol B, bovistol D and strossmayerin: Sesquiterpene metabolites from the culture filtrate of the basidiomycete Coprinopsis strossmayeri. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229925"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.phytochem.2003.10.023","article-title":"Four illudane sesquiterpenes from Coprinopsis episcopalis","volume":"65","author":"Reina","year":"2004","journal-title":"Phytochemistry"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.fitote.2018.10.022","article-title":"Emericellins A and B: Two sesquiterpenoids with an unprecedented tricyclo[4,4,2,1]hendecane scaffold from the liquid cultures of endophytic fungus Emericella sp. XL 029","volume":"131","author":"Pang","year":"2018","journal-title":"Fitoterapia"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"898976","DOI":"10.3389\/fmicb.2022.898976","article-title":"Enhancing the discovery of bioactive secondary metabolites from fungal endophytes using chemical elicitation and variation of fermentation media","volume":"13","author":"Gakuubi","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s12223-018-0587-2","article-title":"Bioprospecting of Diaporthe terebinthifolii LGMF907 for antimicrobial compounds","volume":"63","author":"Savi","year":"2018","journal-title":"Folia Microbiol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1016\/j.phytochem.2008.02.002","article-title":"Chemistry and weak antimicrobial activities of phomopsins produced by mangrove endophytic fungus Phomopsis sp. ZSU-H76","volume":"69","author":"Huang","year":"2008","journal-title":"Phytochemistry"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e6427","DOI":"10.7717\/peerj.6427","article-title":"Production of eugenol from fungal endophytes Neopestalotiopsis sp. and Diaporthe sp. isolated from Cinnamomum loureiroi leaves","volume":"7","author":"Tanapichatsakul","year":"2019","journal-title":"PeerJ"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Ulanowska, M., and Olas, B. (2021). Biological properties and prospects for the application of eugenol\u2014A review. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073671"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.sajb.2020.02.033","article-title":"Isolation of potential antimicrobial metabolites from endophytic fungus Cladosporium cladosporioides from endemic plant Zygophyllum mandavillei","volume":"134","author":"Yehia","year":"2020","journal-title":"S. Afr. J. Bot."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41579-021-00631-7","article-title":"New keys to unlock the treasure trove of microbial natural products","volume":"19","author":"Udwary","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41589-019-0400-9","article-title":"A computational framework to explore large-scale biosynthetic diversity","volume":"16","author":"Mullowney","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"ref_119","unstructured":"Kumar, A., Bilal, M., Ferreira, L.F.R., and Kumari, M. (2023). Chapter 7\u2013Actinomycetes, cyanobacteria, and fungi: A rich source of bioactive molecules. Microbial Biomolecules, Academic Press."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13059-017-1151-0","article-title":"Comparative genomics reveals high biological diversity and specific adaptations in the industrially and medically important fungal genus Aspergillus","volume":"18","author":"Riley","year":"2017","journal-title":"Genome Biol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"107345","DOI":"10.1016\/j.biotechadv.2019.02.001","article-title":"On top of biosynthetic gene clusters: How epigenetic machinery influences secondary metabolism in fungi","volume":"37","author":"Pfannenstiel","year":"2019","journal-title":"Biotechnol. Adv."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/microbiolspec.FUNK-0052-2016","article-title":"Fungal diversity revisited: 2.2 to 3.8 million species","volume":"5","author":"Hawksworth","year":"2017","journal-title":"Microbiol. Spectr."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Selzer, P.M., Marh\u00f6fer, R.J., and Koch, O. (2018). Comparative genome analyses. Applied Bioinformatics, Springer.","DOI":"10.1007\/978-3-319-68301-0"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1007\/s00203-019-01806-w","article-title":"Vesicular transport and secretion of penicillin G in Penicillium rubens P2-32-T","volume":"202","author":"Campos","year":"2020","journal-title":"Arch. Microbiol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/BF00173993","article-title":"Utilization of side-chain precursors for penicillin biosynthesis in a high-producing strain of Penicillium chrysogenum","volume":"40","author":"Jensen","year":"1994","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"100560","DOI":"10.1016\/j.mtbio.2023.100560","article-title":"Unlocking the magic in mycelium: Using synthetic biology to optimize filamentous fungi for biomanufacturing and sustainability","volume":"19","author":"Jo","year":"2023","journal-title":"Mater. Today Bio"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1002\/cbic.201000259","article-title":"First heterologous reconstruction of a complete functional fungal biosynthetic multigene cluster","volume":"11","author":"Heneghan","year":"2010","journal-title":"ChemBioChem"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s00253-016-8034-2","article-title":"Natural products from filamentous fungi and production by heterologous expression","volume":"101","author":"Alberti","year":"2017","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.biortech.2003.10.018","article-title":"Citric acid production by selected mutants of Aspergillus niger from cane molasses","volume":"93","author":"Ali","year":"2004","journal-title":"Bioresour. Technol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s12934-021-01659-3","article-title":"Improving citric acid production of an industrial Aspergillus niger CGMCC 10142: Identification and overexpression of a high-affinity glucose transporter with different promoters","volume":"20","author":"Xue","year":"2021","journal-title":"Microb. Cell Factories"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1016\/j.csbj.2021.06.030","article-title":"Integration strategies of multi-omics data for machine learning analysis","volume":"19","author":"Picard","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/nrg1637","article-title":"Synthetic biology","volume":"6","author":"Benner","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Estrada, C., Mart\u00edn, J.F., Cueto, L., and Barreiro, C. (2020). Omics approaches applied to Penicillium chrysogenum and penicillin production: Revealing the secrets of improved productivity. Genes, 11.","DOI":"10.3390\/genes11060712"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"e01561-19","DOI":"10.1128\/AEM.01561-19","article-title":"Impact of classical strain improvement of Penicillium rubens on amino acid metabolism during \u03b2-Lactam production","volume":"86","author":"Wu","year":"2019","journal-title":"Appl. Environ. Microbiol."}],"updated-by":[{"DOI":"10.3390\/antibiotics13100944","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T00:00:00Z","timestamp":1690588800000}}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/8\/1250\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T14:44:49Z","timestamp":1754232289000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/8\/1250"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,29]]},"references-count":134,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["antibiotics12081250"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics12081250","relation":{"correction":[{"id-type":"doi","id":"10.3390\/antibiotics13100944","asserted-by":"object"}]},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,29]]}}}