Open Access Open Access  Restricted Access Subscription Access

The War against MDR Pathogens:Move Fungi to the Frontline


Affiliations
1 Vivekananda Institute of Tropical Mycology, RKM Vidyapith, Chennai 600 004, India
2 Department of Comparative Plant and Fungal Biology, Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3DS, United Kingdom
 

The evolution and spread of resistance among pathogenic microbes to different antibiotics currently in use is a global health problem. Attempts are being made to tackle this major health burden by involving policy makers, scientists, healthcare professionals, the general public and industry. Several strategies, including improvement of prescribing practices, use of combination therapies and synthetic antibiotics, and development of species-specific antibiotics have been suggested to retard the evolution of drug resistance. However, most of the new antibiotic molecules which are being prepared to be marketed are only modifications of existing ones, thus lacking novelty in their mechanism of action or target sites. It is reasonable to expect that the introduction of totally new antibiotics would delay the evolution of drug resistance. In this context, the filamentous fungi are a promising source of novel antibiotics. Their diverse biochemical pathways, the range of ecological niches they occupy, and that 8% or less of the 2.2–3.8 million estimated fungal species are known, underscore the now urgent need to screen them for novel antibiotics.

Keywords

Drug Resistance, Filamentous Fungi, Novel Antibiotics, Pathogenic Microbes.
User
Notifications
Font Size

  • Kumarasamy, K. K. et al., Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect. Dis., 2010, 10, 597–602.
  • Ventola, C. L., The antibiotic resistance crisis. Part 1: causes and threats. Pharm. Ther., 2015, 40, 277–283.
  • The Review on Antimicrobial Resistance. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. 2014, pp. 1–20; https://maerreview.org/sites/default/files/AMR%20Review20Review%20Paper%20%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf
  • Sharma, A. et al., Estimating the future burden of multidrugresistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study. Lancet Infect. Dis., 2017, 17, 707–715.
  • Martens, E. and Demain, A. L., The antibiotic resistance crisis, with a focus on the United States. J. Antibiot., 2017, 70, 520–526.
  • Fair, R. J. and Tor, Y., Antibiotics and bacterial resistance in the 21st century. Perspect. Med. Chem., 2014, 6, 25–64.
  • Fischbach, M. A. and Walsh, C. T., Antibiotics for emerging pathogens. Science, 2009, 325, 1089–1093.
  • Hawksworth, D. L. and Dentinger, B. T. M., Antibiotics: relax UK import rule on fungi. Nature, 2013, 496, 169.
  • Davies, J., What are antibiotics? Archaic functions for modern activities. Mol. Microbiol., 1990, 4, 1227–1232.
  • Hibbing, M. E., Fuqua, C., Parsek, M. R. and Peterson, S. B., Bacterial competition: surviving and thriving in the microbial jungle. Nature Rev. Microbiol., 2010, 8, 15–25.
  • Wiener, P., Experimental studies on the ecological role of antibiotic production in bacteria. Evol. Ecol., 1996, 10, 405–421.
  • Aminov, R. I. and Mackie, R. I., Evolution and ecology of antibiotic resistance genes. FEMS Microbiol. Lett., 2007, 271, 147– 161.
  • Wang, R. et al., The global distribution and spread of the mobilized colistin resistance gene mcr-1. Nature Commun., 2018, 9, 1179; doi:10.1038/s41467-018-03205-z
  • Hiltunen, T., Virta, M. and Laine, A.-L., Antibiotic resistance in the wild: an eco-evolutionary perspective. Philos. Trans. R. Soc. London, Ser. B, 2017, 372, 20160039; http://dx.doi.org/10.1098/rstb.2016.0039
  • Munita, J. M. and Arias, C. A., Mechanisms of antibiotic resistance. Microbiol. Spectr., 2016, 4; doi:10.1128/microboilspec.VMBF-0016-2015.
  • Belousoff, M. J. et al., Structural basis for linezolid binding site rearrangement in the Staphylococcus aureus ribosome. mBio, 2017, 8, e00395-17; https://doi.org/10.1128/mBio.00395-17.
  • Ventola, C. L., The antibiotic resistance crisis: Part 2: management strategies and new agents. Pharm. Ther., 2015, 40, 344–352.
  • Chiang, C-Y., Uzoma, I., Moore, R. T., Gilbert, M., Duplantier, A. J. and Panchal, R. G., Mitigating the impact of antibacterial drug resistance through host-directed therapies: current progress, outlook, and challenges. mBio, 2018, 9, e01932-17; https://doi.org/ 10.1128/mBio.01932-17.
  • Seiple, I. B. et al., A platform for the discovery of new macrolide antibiotics. Nature, 2016, 533, 338–345.
  • Onaka, H., Novel antibiotic screening methods to awaken silent or cryptic secondary metabolic pathways in actinomycetes. J. Antibiot., 2017, 70, 865–870.
  • Wilson, D. N. et al., Species-specific antibiotic–ribosome interactions: implications for drug development. Biol. Chem., 2005, 386, 1239–1252.
  • Lewis, K., Platforms for antibiotic discovery. Nature Rev. Drug Discov., 2013, 12, 371–387.
  • Rossolini, G. M. and Thaller, M. C., Coping with antibiotic resistance: contributions from genomics. Genome Med., 2010, 2, 15.
  • Hover, B. M. et al., Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrugresistant Gram-positive pathogens. Nature Microbiol., 2018, 3, 415–422.
  • Simpkin, V. L., Renwick, M. J., Kelly, R. and Mossialos, E., Incentivising innovation in antibiotic drug discovery and development: progress, challenges and next steps. J. Antibiot., 2017, 70, 1087–1096.
  • Moskvitch, K., How to solve the problem of antibiotic resistance. Sci. Am., 2015, 28; https://www.scientificamerican.com/article/how-to-solve-the-problem-of-antibiotic-resistance/
  • Stern, S., Chorzelski, S., Franken, L., Völler, S., Rentmeister, H. and Grosch, B., Breaking through the wall: A call for concerted action on antibiotics research and development, The Boston Consulting, Group, Berlin, 2017, pp. 1–80.
  • Renwick, M. J., Simpkin, V. and Mossialos, E., Targeting innovation in antibiotic drug discovery and development: the need for a one health, one Europe, one world framework. European Observatory on Health Systems and Policies, Copenhagen, Denmark, Health Policy Series No. 45, 2016, pp. 1–133.
  • Ling, L. L. et al., A new antibiotic kills pathogens without detectable resistance. Nature, 2015, 517, 455–459.
  • Wright, G. D., Solving the antibiotic crisis. ACS Infect. Dis., 2015, 1, 80–84.
  • Ho, W. H., To, P. C. and Hyde, K. D., Induction of antibiotic production of freshwater fungi using mix-culture fermentation. Fungal Divers., 2003, 12, 45–51.
  • Hyde, K. D., Increasing the likelihood of novel compound discovery from filamentous fungi. In Bio-exploitation of Filamentous Fungi (eds Pointing, S. B. and Hyde, K. D.), Fungal Diversity Research Series 6, Fungal Diversity Press, Hong Kong, 2001, pp. 77–91.
  • Macheleidt, J. et al., Regulation and role of fungal secondary metabolites. Annu. Rev. Genet., 2016, 50, 371–392.
  • Kück, U., Bloemendal, S. and Teichert, I., Putting fungi to work: harvesting a cornucopia of drugs, toxins, and antibiotics. PLoS Pathog., 2014, 10, e1003950; https://doi.org/10.1371/journal.ppat.1003950.
  • Hawksworth, D. L. and Lücking, R., Fungal diversity revisited: 2.2 to 3.8 million species. In The Fungal Kingdom (eds Heitman, J. et al.), ASM Press, Washington, USA, 2018, pp. 79–95.
  • Bugni, T. S. and Ireland, C. M., Marine-derived fungi: a chemically and biologically diverse group of microorganisms. Nat. Prod. Rep., 2004, 21, 143–163.
  • Sugie, Y. et al., CJ-15,801, a novel antibiotic from a fungus, Seimatosporium sp. J. Antibiot., 2001, 54, 1060–1065.
  • Kaushik, N. K., Murali, T. S., Sahal, D. and Suryanarayanan, T. S., A search for antiplasmodial metabolites among fungal endophytes of terrestrial and marine plants of southern India. Acta Parasitol., 2014, 59, 745–757.
  • Chang, W., Zhang, M., Li, Y., Li, X., Gao, Y., Xie, Z. and Lou, H., Lichen endophyte derived pyridoxatin inactivates Candida growth by interfering with ergosterol biosynthesis. Biochim. Biophys. Acta, 2015, 1850, 1762–1771.
  • Yedukondalu, N. et al., Diapolic acid A–B from an endophytic fungus, Diaporthe terebinthifolii depicting antimicrobial and cytotoxic activity. J. Antibiot., 2017, 70, 212–215.
  • Adelin, E., Le Goff, G., Retailleau, P., Bonfill, M. and Ouazzani, J., Isolation of the antibiotic methyl (R,E)-3-(1-hydroxy-4oxocyclopent-2-en-1-yl)-acrylate EA-2801 from Trichoderma atroviridae. J. Antibiot., 2017, 70, 1053–1056.
  • Takahashi, K. et al., Cladomarine, a new anti-saprolegniasis compound isolated from the deep-sea fungus, Penicillium coralligerum YK-247. J. Antibiot., 2017, 70, 911–914.
  • Wang, Y.-T., Xue, Y.-R. and Liu, C.-H., A brief review of bioactive metabolites derived from deep-sea fungi. Mar. Drugs, 2015, 13, 4594–4616.
  • Wang, J. et al., Screening of anti-biofilm compounds from marinederived fungi and the effects of secalonic acid D on Staphylococcus aureus biofilm. J. Microbiol. Biotechnol., 2017, 27, 1078–1089.
  • Gao, X.-W., Liu, H.-X., Sun, Z.-H., Che, Y.-C., Tan, Y.-Z. and Zhang, W.-M., Secondary metabolites from the deep-sea derived fungus Acaromyces ingoldii FS121. Molecules, 2016, 21, 371.
  • He, K.-Y. et al., New chlorinated xanthone and anthraquinone produced by a mangrove-derived fungus Penicillium citrinum HL5126. J. Antibiot., 2017, 70, 823–827.
  • Suryanarayanan, T. S., Venkatachalam, A., Thirunavukkarasu, N., Ravishankar, J. P., Doble, M. and Geetha, V., Internal mycobiota of marine macroalgae from the Tamilnadu coast: distribution, diversity and biotechnological potential. Bot. Mar., 2010, 53, 456– 468.
  • Suryanarayanan, T. S., The diversity and importance of fungi associated with marine sponges. Bot. Mar., 2012, 55, 553–564.
  • Thirunavukkarasu, N., Suryanarayanan, T. S., Girivasan, K. P., Venkatachalam, A., Geetha, V., Ravishankar, J. P. and Doble, M., Fungal symbionts of marine sponges from Rameswaram, southern India: species composition and bioactive metabolites. Fungal Divers., 2012, 55, 37–46.
  • Ookura, R., Kito, K., Ooi, T., Namikoshi, M. and Kusumi, T., Structure revision of circumdatins A and B, benzodiazepine alkaloids produced by marine fungus Aspergillus ostianus by X-ray crystallography. J. Org. Chem., 2008, 73, 4245–4247.
  • Wiese, J. et al., Phylogenetic identification of fungi isolated from the marine sponge Tethya aurantium and identification of their secondary metabolites. Mar. Drugs, 2011, 9, 561–585.
  • Karwehl, S. and Stadler, M., Exploitation of fungal biodiversity for discovery of novel antibiotics. In How to Overcome the Antibiotic Crisis (eds Stadler, M. and Dersch, P.), Curr. Top. Microbiol. Immunol., 2016, 398, 303–338.
  • Suryanarayanan, T. S. and Hawksworth, D. L., Fungi from littleexplored and extreme habitats. In Bio-Diversity of Fungi: Their Role in Human Life (eds Deshmukh, S. K. and Rai, M. K.), Oxford & IBH Publishing, 2005, pp. 33–48.
  • Liu, T. et al., Two new amides from a halotolerant fungus, Myrothecium sp. GS-17. J. Antibiot., 2015, 68, 267–270.
  • Lu, X.-L. et al., Pimarane diterpenes from the arctic fungus Eutypella sp. D-1. J. Antibiot., 2014, 67, 171–174.
  • Chávez, R., Fierro, F., García-Rico, R. O. and Vaca, I., Filamentous fungi from extreme environments as a promising source of novel bioactive secondary metabolites. Front. Microbiol., 2015, 6, 903.
  • Blackwell, M., Made for each other: ascomycete yeasts and insects. In The Fungal Kingdom (eds Heitman, J. et al.), ASM Press, Washington, USA, 2018, pp. 945–962.
  • Bao, J. et al., Antifouling and antibacterial polyketides from marine gorgonian coral-associated fungus Penicillium sp. SCSGAF 0023. J. Antibiot., 2013, 66, 219–223.
  • He, H., Bigelis, R., Yang, H. Y., Chang, L.-P. and Singh, M. P., Lichenicolins A and B, new bisnaphthopyrones from an unidentified lichenicolous fungus, strain LL-RB0668. J. Antibiot., 2005, 58, 731–736.
  • Suryanarayanan, T. S., Govindarajulu, M. B., Rajamani, T., Tripathi, M. and Joshi, Y., Endolichenic fungi in lichens of Champawat district, Uttarakhand, northern India. Mycol. Prog., 2017, 16, 205–211.
  • Chepkirui, C. and Stadler, M., The genus Diaporthe: a rich source of diverse and bioactive metabolites. Mycol. Prog., 2017, 16, 477– 494.
  • Andersen, M. R. et al., Accurate prediction of secondary metabolite gene clusters in filamentous fungi. Proc. Natl. Acad. Sci. USA, 2013, 110, E99–E107.
  • Hemphill, C. F. P., Sureechatchaiyan, P., Kassack, M. U., Orfali, R. S., Lin, W., Daletos, G. and Proksch, P., OSMAC approach leads to new fusarielin metabolites from Fusarium tricinctum. J. Antibiot., 2017, 70, 726–732.
  • Brakhage, A. A. and Schroeckh, V., Fungal secondary metabolites – Strategies to activate silent gene clusters. Fungal Genet. Biol., 2011, 48, 15–22.
  • Connolly, L. R., Smith, K. M. and Freitag, M., The Fusarium graminearum histone H3 K27 methyltransferase KMT6 regulates development and expression of secondary metabolite gene clusters. PLoS Genet., 2013, 9, e1003916.
  • Smith, K. M., Gautschi, J. T. and Freitag, M., Decoding the cryptic genomes of fungi: the promise of novel antibiotics. Future Microbiol., 2014, 9, 265–268.
  • Thaker, M. N. and Wright, G. D., Opportunities for synthetic biology in antibiotics: expanding glycopeptide chemical diversity. ACS Synth. Biol., 2015, 20, 195–206.
  • Bills, G. F. et al., Enhancement of antibiotic and secondary metabolite detection from filamentous fungi by growth on nutritional arrays. J. Appl. Microbiol., 2008, 104, 1644–1658.
  • Scherlach, K. and Hertweck, C., Discovery of aspoquinolones A–D, prenylated quinoline-2-one alkaloids from Aspergillus nidulans, motivated by genome mining. Org. Biomol. Chem., 2006, 4, 3517–3520.
  • Stierle, A. A. et al., The berkeleylactones, antibiotic macrolides from fungal coculture. J. Nat. Prod., 2017, 80, 1150–1160.
  • Nielsen, J. C. et al., Global analysis of biosynthetic gene clusters reveals vast potential of secondary metabolite production in Penicillium species. Nature Microbiol., 2017, 2, article number: 17044.

Abstract Views: 336

PDF Views: 110




  • The War against MDR Pathogens:Move Fungi to the Frontline

Abstract Views: 336  |  PDF Views: 110

Authors

T. S. Suryanarayanan
Vivekananda Institute of Tropical Mycology, RKM Vidyapith, Chennai 600 004, India
D. L. Hawksworth
Department of Comparative Plant and Fungal Biology, Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3DS, United Kingdom

Abstract


The evolution and spread of resistance among pathogenic microbes to different antibiotics currently in use is a global health problem. Attempts are being made to tackle this major health burden by involving policy makers, scientists, healthcare professionals, the general public and industry. Several strategies, including improvement of prescribing practices, use of combination therapies and synthetic antibiotics, and development of species-specific antibiotics have been suggested to retard the evolution of drug resistance. However, most of the new antibiotic molecules which are being prepared to be marketed are only modifications of existing ones, thus lacking novelty in their mechanism of action or target sites. It is reasonable to expect that the introduction of totally new antibiotics would delay the evolution of drug resistance. In this context, the filamentous fungi are a promising source of novel antibiotics. Their diverse biochemical pathways, the range of ecological niches they occupy, and that 8% or less of the 2.2–3.8 million estimated fungal species are known, underscore the now urgent need to screen them for novel antibiotics.

Keywords


Drug Resistance, Filamentous Fungi, Novel Antibiotics, Pathogenic Microbes.

References





DOI: https://doi.org/10.18520/cs%2Fv115%2Fi12%2F2201-2205