Innovations in Microbial Biodiscovery, Targeting Silent Metabolism and New Chemical Diversity

Zeinab G. Khalil, Robert J. Capon

Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia; The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD 4102, AustraliaAustralia
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, AustraliaAustralia

DOI: https://doi.org/10.17140/vroj-1-104 · Published 2016-09-07 · Licence: https://creativecommons.org/licenses/by/4.0 · © 2016 The Author(s)

Also available as PDF (figures and tables appear in the PDF).

Keywords: Microbial biodiscovery; Antibiotics; Anticancer; Silent metabolism; Lipopolysaccharide; Lipopoly - saccharide

Conclusion

Nature is a good source and producer of small molecules that have a great interaction with biological targets. Despite that natural products continue to provide more than half of all new drugs approved by the US Food and Drug Administration (FDA) during the last century, there is a huge shift in finding a new molecules to overcome the threat coming from multi-drug resistance bacteria and cancer resistant cells.

The decline in the pipeline for the discovery of new microbial metabolites can be attributed to the continuous rediscovery of known metabolites and we believe that the main reason for the decline in the discovery of new biologically active compounds can be that many of the microbial genes can remain dormant under normal laboratory conditions. Therefore, the microbe may require an external stimuli in order to start behave in different way and try to produce different chemistry. In fact, modern genomics have opened the tools and brighten our understanding of the microbial secondary metabolism. Medema et al69 have demonstrated a computational analysis of the microbial metabolism through comprising approximately 300 microbial genome, which lead to the prediction of thousands of microbial genome sequencing. This great outcome provides the opportunity for the acquisition of the full microbial genome and the availability of high throughput sequencing technologies with modern analytical instrumentation allowed to determine or postulate the type of metabolites that can be produced by any microorganisms.

Therefore, we found that it is worthwhile to try to find a new paradigm for drug discovery to help to overcome the limited laboratory conditions and to establish a new technique to target the production of antibiotics. In order to perform such paradigm, we established a combinatorial chemical libraries in order to cover much chemical space to increase the probability of wakening up the silent genes and turning on new secondary metabolites.

Conflicts Of Interest

The authors declare that they have no conflicts of interest.

References

1. NewmanDJCraggGMSnaderKM. Natural products as sources of new drugs over the period 1981-2002. J Nat Prod. 2003; 66: 1022-1037. doi: 10.1021/np030096l10.1021/np030096l https://doi.org/10.1021/np030096l
2. BerdyJ. Bioactive microbial metabolites: A personal view. J Antibiot. 2005; 58: 1-26. Web site. http://crawl.prod.proquest. com.s3.amazonaws.com/fpcache/e406c496973d03e7326281ef- 3a3966fe.pdf?AWSAccessKeyId=AKIAJF7V7KNV2KKY2N UQ&Expires=1472901756&Signature=4pJT%2BHcesaq2Aou FMa%2FioR47ss0%3D. Accessed August 28, 2016
3. PelaezF. The historical delivery of antibiotics from microbial natural products-Can history repeat? Biochem Pharmacol. 2006; 71: 981-990
4. BakerDDChuMOzaURajgarhiaV. The value of natural products to future pharmaceutical discovery. Nat Prod Rep. 2007; 24: 1225-1244. doi: 10.1039/b602241n10.1039/b602241n https://doi.org/10.1039/b602241n
5. LazzariniACavalettiLToppoGMarinelliF. Rare genera of actinomycetes as potential producers of new antibiotics. Antonie van Leeuwenhoek. 2000; 78: 399-405. doi: 10.1023/ A:1010287600557
6. CaponRJ. Microbial biodiscovery: Back to the future. Curr Top Med Chem. 2012; 12: 1471-1478. doi: 10.2174/ 156802612802652394
7. ClatworthyAEPiersonEHungDT. Targeting virulence: A new paradigm for antimicrobial therapy. Nat Chem Biol. 2007; 3: 541-548. doi: 10.1038/nchembio.2007.2410.1038/nchembio.2007.24 https://doi.org/10.1038/nchembio.2007.24
8. HobanDJBouchillonSKJohnsonBMJohnsonJLDowzickyMJ. In vitro activity of tigecycline against 6792 Gramnegative and Gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST Program, 2004). Diagn. Microbiol Infect Dis. 2005; 52: 215-227. doi: 10.1016/j.diagmicrobio.2005.06.00110.1016/j.diagmicrobio.2005.06.001 https://doi.org/10.1016/j.diagmicrobio.2005.06.001
9. DraghiDCTenchSDowzickyMJSahmDF. Baseline in vitro activity of tigecycline among key bacterial pathogens exhibiting multidrug resistance. Chemotherapy. 2008; 54: 91-100. Page 21 doi: 10.1159/00011866010.1159/000118660 https://doi.org/10.1159/000118660
10. WangJSoissonSMYoungK. Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature. 2006; 441: 358-361. doi: 10.1038/nature0478410.1038/nature04784 https://doi.org/10.1038/nature04784
11. JayasuriyaHHerathKBZhangC. Isolation and structure of Platencin: A FabH and FabF dual inhibitor with potent broad-spectrum antibiotic activity. Angewandte Chemie. 2007; 46: 4684-4688
12. SinghSBJayasuriyaHOndeykaJG. Isolation, structure, and absolute stereochemistry of platensimycin, a broad spectrum antibiotic discovered using an antisense differential sensitivity strategy. J Am Chem Soc. 2006; 128: 11916-11920. doi: 10.1021/ja062232p10.1021/ja062232p https://doi.org/10.1021/ja062232p
13. WangJKodaliSLeeSH. Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties. Proc. Natl Acad Sci USA. 2007; 104: 7612-7616. doi: 10.1073/ pnas.0700746104
14. ZhangCOndeykaJZinkDLBurgessBWangJSinghSB. Isolation, structure and fatty acid synthesis inhibitory activities of platensimycin B1-B3 from Streptomyces platensis. Chem Commun (Camb). 2008: 5034-5036. doi: 10.1039/b810113b10.1039/b810113b https://doi.org/10.1039/b810113b
15. ZhangCOndeykaJGuanZ. Isolation, structure and biological activities of platensimycin B4 from Streptomyces platensis. J Antibiot. 2009; 62: 699-702. doi: 10.1038/ja.2009.10610.1038/ja.2009.106 https://doi.org/10.1038/ja.2009.106
16. JacobMRWalkerLA. Natural products and antifungal drug discovery. Methods Mol Med. 2005; 118: 83-109. doi: 10.1385/1-59259-943-5:08310.1385/1-59259-943-5:083 https://doi.org/10.1385/1-59259-943-5:083
17. DeresinskiSCStevensDA. Caspofungin. Clinical Infec tious Diseases. 2003; 36: 1445-1457. doi: 10.1086/37508010.1086/375080 https://doi.org/10.1086/375080
18. Westby M, van Dre. CCR5 antagonists: Host-targeted anti virals for the treatment of HIV infection. Antiviral Chem Chemother. 2005; 16: 339-354. doi: 10.1177/095632020501600601 https://doi.org/10.1177/095632020501600601
19. ZiolkowskaNEWlodawerA. Structural studies of algal lectins with anti-HIV activity. Acta Biochim Pol. 2006; 53: 617- 626. Web site. http://www.actabp.pl/pdf/4_2006/617.pdf. Accessed August 29, 2016
20. HalfonP. Treatment of hepatitis C virus related diseases using hydroxychloroquine or a combination of hydroxychloroquine and an anti-viral agent. Patent Docs. 2011. Web site. http:// www.patentsencyclopedia.com/imgfull/20130121965_01. Accessed August 29, 2016
21. Yu D, Morris-Natschke SL, Lee K-H. New developments in natural products-based anti-AIDS research. Med Res Rev. 2007; 27: 108-132
22. TaubesG. The bacteria fight back. Science. 2008; 321: 356- 361. doi: 10.1126/science.321.5887.35610.1126/science.321.5887.356 https://doi.org/10.1126/science.321.5887.356
23. ChaitRVetsigianKKishonyR. What counters antibiotic resistance in nature? Nat Chem Biol. 2012; 8: 2-5. doi: 10.1038/ nchembio.745
24. D’CostaVMKingCEKalanL. Antibiotic resistance is ancient. Nature. 2011; 477: 457-461. doi: 10.1038/nature1038810.1038/nature10388 https://doi.org/10.1038/nature10388
25. AllenHKDonatoJWangHHCloud-HansenKADaviesJHandelsmanJ. Call of the wild: Antibiotic resistance genes in natural environments. Nat Rev Microbiol. 2010; 8: 251-259. doi: 10.1038/nrmicro231210.1038/nrmicro2312 https://doi.org/10.1038/nrmicro2312
26. WrightGD. Antibiotic resistance in the environment: A link to the clinic? Curr Opin Microbiol. 2010; 13: 589-594. doi: 10.1016/j.mib.2010.08.00510.1016/j.mib.2010.08.005 https://doi.org/10.1016/j.mib.2010.08.005
27. GottesmanMMFojoTBatesSE. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer. 2002; 2: 48-58. doi: 10.1038/nrc70610.1038/nrc706 https://doi.org/10.1038/nrc706
28. Qin T, Skraba-Joiner SL, Khalil ZG, Johnson RP, Capon RJ, Porco JA, Jr. Atropselective syntheses of (-) and (+) rugulotrosin A utilizing point-to-axial chirality transfer. Nat Chem. 2015; 7: 234-240. doi: 10.1038/nchem.2173 https://doi.org/10.1038/nchem.2173
29. ShangZKhalilZLiL. Roseopurpurins: Chemical diversity enhanced by convergent biosynthesis and forward and reverse michael additions. Org Lett. 2016; 18: 4340-4343. doi: 10.1021/acs.orglett.6b0209910.1021/acs.orglett.6b02099 https://doi.org/10.1021/acs.orglett.6b02099
30. ShangZSalimAAKhalilZBernhardtPVCaponRJ. Fungal biotransformation of tetracycline antibiotics. J Org Chem. 2016; 81: 6186-6194. doi: 10.1021/acs.joc.6b0127210.1021/acs.joc.6b01272 https://doi.org/10.1021/acs.joc.6b01272
31. KhalilZGRajuRPiggottAM. Antimycobacterial Anthracyclines from an Australian Marine-Derived Streptomyces sp. J Nat Prod. 2015; 78: 949-952. doi: 10.1021/acs. jnatprod.5b0009510.1021/acs.jnatprod.5b00095 https://doi.org/10.1021/acs.jnatprod.5b00095
32. Bok JW, Chiang Y-M, Szewczyk E, et al. Chromatin-level regulation of biosynthetic gene clusters. Nat Chem Biol. 2009; 5: 462-464. doi: 10.1038/nchembio.177 https://doi.org/10.1038/nchembio.177
33. ScherlachKHertweckC. Triggering cryptic natural product biosynthesis in microorganisms. Org Biomol Chem. 2009; 7: 1753-1760. doi: 10.1039/b821578b10.1039/b821578b https://doi.org/10.1039/b821578b
34. OmuraSIkedaHIshikawaJ. Genome sequence of an industrial microorganism Streptomyces avermitilis: Deducing the ability of producing secondary metabolites. Proc Natl Acad Sci USA. 2001; 98: 12215-12220. doi: 10.1073/pnas.211433198 Page 2210.1073/pnas.211433198 https://doi.org/10.1073/pnas.211433198
35. BentleySDChaterKFCerdeno-TarragaAM. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature. 2002; 417: 141-147. doi: 10.1038/417141a10.1038/417141a https://doi.org/10.1038/417141a
36. McAlpineJBBachmannBOPiraeeM. Microbial genomics as a guide to drug discovery and structural elucida tion: ECO-02301, a novel antifungal agent, as an example. J Nat Prod. 2005; 68: 493-496. doi: 10.1021/np040166410.1021/np0401664 https://doi.org/10.1021/np0401664
37. UdwaryDWZeiglerLAsolkarRN. Genome sequencing reveals complex secondary metabolome in the marine acti nomycete Salinispora tropica. Proc Natl Acad Sci USA. 2007; 104: 10376-10381. doi: 10.1073/pnas.070096210410.1073/pnas.0700962104 https://doi.org/10.1073/pnas.0700962104
38. ElanderRP. Industrial production of β-lactam antibiotics. Appl Microbiol Biotechnol. 2003; 61: 385-392. doi: 10.1007/ s00253-003-1274-y
39. ParanagamaPAWijeratneEMKGunatilakaAAL. Uncovering biosynthetic potential of plant-associated fungi: Effect of culture conditions on metabolite production by paraphaeosphaeria quadriseptata and chaetomium chiversii. J Nat Prod. 2007; 70: 1939-1945. doi: 10.1021/np070504b10.1021/np070504b https://doi.org/10.1021/np070504b
40. AyerSWMcInnesAGThibaultP. Jadomycin, a novel 8H-benz[b]oxazolo[3,2-f]phenanthridine antibiotic from Streptomyces venezuelae ISP5230. Tetrahedron Lett. 1991; 32: 6301- 6304
41. DoullJLSinghAKHoareMAyerSW. Conditions for the production of jadomycin B by Streptomyces venezuelae ISP5230: Effects of heat shock, ethanol treatment and phage infection. J Ind Microbiol. 1994; 13: 120-125. doi: 10.1007/ BF01584109
42. OveryDPSmedsgaardJFrisvadJCPhippsRKThraneU. Host-derived media used as a predictor for low abundant, in planta metabolite production from necrotrophic fungi. J Appl Microbiol. 2006; 101: 1292-1300
43. CuetoMJensenPRKauffmanCFenicalWLobkovskyEClardyJ. Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge. J Nat Prod. 2001; 64: 1444-1446. doi: 10.1021/np010271310.1021/np0102713 https://doi.org/10.1021/np0102713
44. Chiang Y-M, Szewczyk E, Nayak T, et al. Molecular genetic mining of the aspergillus secondary metabolome: Discovery of the emericellamide biosynthetic pathway. Chem Biol. 2008; 15: 527-532. doi: 10.1016/j.chembiol.2008.05.010 https://doi.org/10.1016/j.chembiol.2008.05.010
45. LatifiAWinsonMKFoglinoM. Multiple homologs of LuxR and LuxI control expression of virulence determinants and secondary metabolites through quorum sensing in Pseudomonas aeruginosa PAO1. Mol Microbiol. 1995; 17: 333-343
46. BodeHB. No need to be pure: Mix the cultures! Chem Biol. 2006; 13: 1245-1246
47. CaponRJ. Microbial biodiscovery: Back to the future. Curr Top Med Chem. 2012; 12: 1471-1478. doi: 10.2174/15680 261280265239410.2174/15680 https://doi.org/10.2174/15680
48. HorinouchiSBeppuT. Autoregulatory factors and communication in actinomycetes. Annu Rev Microbiol. 1992; 46: 377- 398. doi: 10.1146/annurev.mi.46.100192.00211310.1146/annurev.mi.46.100192.002113 https://doi.org/10.1146/annurev.mi.46.100192.002113
49. KleinerEMPlinerSASoiferVS. Structure of the A factor, a bioregulator from Streptomyces griseus. Bioorg Khim. 1976; 2: 1142-1147
50. HashimotoMKondoTKozoneIKawaideHAbeHNatsumeM. Relationship between response to and production of the aerial mycelium-inducing substances pamamycin-607 and A-factor. Biosci Biotechnol Biochem. 2003; 67: 803-808. doi: 10.1271/bbb.67.80310.1271/bbb.67.803 https://doi.org/10.1271/bbb.67.803
51. RecioEColinasARumberoAAparicioJFMartinJF. PI factor, a novel type quorum-sensing inducer elicits pimaricin production in Streptomyces natalensis. J Biol Chem. 2004; 279: 41586-41593. doi: 10.1074/jbc.M40234020010.1074/jbc.m402340200 https://doi.org/10.1074/jbc.m402340200
52. OnakaHTabataHIgarashiYSatoYFurumaiT. Goadsporin, a chemical substance which promotes secondary metabo lism and morphogenesis in streptomycetes. I. Purification and characterization. J Antibiot. 2001; 54: 1045-1053. doi: 10.7164/ antibiotics.54.1045
53. AsadSOpalSM. Bench-to-bedside review: Quorum sensing and the role of cell-to-cell communication during invasive bacterial infection. Crit Care. 2008; 12: 236. doi: 10.1186/cc710110.1186/cc7101 https://doi.org/10.1186/cc7101
54. AntonyMJayachandranK. Regulation of acyl homoser ine lactone synthesis in pseudomonas putida jMQS1 under phenol stress. Water Air and Soil Pollution. 2016; 227: 338. doi: 10.1007/s11270-016-3018-510.1007/s11270-016-3018-5 https://doi.org/10.1007/s11270-016-3018-5
55. HwangICookDMFarrandSK. A new regulatory element modulates homoserine lactone-mediated autoinduction of Ti plasmid conjugal transfer. J Bacteriol. 1995; 177: 449-458. Web site. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC176609/. Accessed August 29, 2016
56. JonesBYuBBaintonNJ. The lux autoinducer regulates the production of exoenzyme virulence determinants in Erwinia carotovora and Pseudomonas aeruginosa. EMBO J. 1993; 12: 2477-2482. Web site. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC413484/. Accessed August 29, 2016
57. XieYLiuZZhangG. A rifampicin-resistant (rpoB) mutation in Pseudomonas protegens Pf-5 strain leads to improved antifungal activity and elevated production of secondary metabolites. Res Microbiol. 2016. Page 23
58. Cheng J, Zhang X-l, Zhao J-Y, Wen M-l, Ding Z-G, Li M-G. Recent progress of study on secondary metabolites of Streptomyces. Zhongguo Kangshengsu Zazhi. 2015; 40: 791-800
59. SenguptaSPramanikAGhoshABhattacharyyaM. Antimicrobial activities of actinomycetes isolated from unexplored regions of Sundarbans mangrove ecosystem. BMC Microbiol. 2015; 15: 170. doi: 10.1186/s12866-015-0495-410.1186/s12866-015-0495-4 https://doi.org/10.1186/s12866-015-0495-4
60. ZazopoulosEHuangKStaffaA. A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nat Biotechnol. 2003; 21: 187-190. doi: 10.1038/nbt78410.1038/nbt784 https://doi.org/10.1038/nbt784
61. ScherlachKHertweckC. Discovery of aspoquinolones A-D, prenylated quinoline-2-one alkaloids from Aspergillus nidulans, motivated by genome mining. Org Biomol Chem. 2006; 4: 3517-3520. doi: 10.1039/B607011F10.1039/b607011f https://doi.org/10.1039/b607011f
62. PerrinRMFedorovaNDBokJW. Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog. 2007; 3: e50. doi: 10.1371/journal.ppat.003005010.1371/journal.ppat.0030050 https://doi.org/10.1371/journal.ppat.0030050
63. BokJWHoffmeisterDMaggio-HallLAMurilloRGlasnerJDKellerNP. Genomic mining for aspergillus natural products. Chem Biol. 2006; 13: 31-37
64. ShwabEKKellerNP. Regulation of secondary metabolite production in filamentous ascomycetes. Mycol Res. 2008; 112: 225-230. doi: 10.1016/j.mycres.2007.08.02110.1016/j.mycres.2007.08.021 https://doi.org/10.1016/j.mycres.2007.08.021
65. Williams RB, Henrikson JC, Hoover AR, Lee AE, Ciche wicz RH. Epigenetic remodeling of the fungal secondary metabolome. Org Biomol Chem. 2008; 6: 1895-1897. doi: 10.1039/ b804701d
66. RaetzCRHWhitfieldC. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002; 71: 635-700. doi: 10.1146/annurev. biochem.71.110601.13541410.1146/annurev.biochem.71.110601.135414 https://doi.org/10.1146/annurev.biochem.71.110601.135414
67. RosenfeldYShaiY. Lipopolysaccharide (Endotoxin)-host defense antibacterial peptides interactions: Role in bacterial resistance and prevention of sepsis. Biochim Biophys Acta. 2006; 1758: 1513-1522
68. KhalilZGKalansuriyaPCaponRJ. Lipopolysaccharide (LPS) stimulation of fungal secondary metabolism. Mycology. 2014; 5: 168-178. doi: 10.1080/21501203.2014.93053010.1080/21501203.2014.930530 https://doi.org/10.1080/21501203.2014.930530
69. Medema MH, Blin K, Cimermancic P, et al. antiSMASH: Rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. 2011; 39: W339-W346. doi: 10.1093/nar/gkr466 Page 24 https://doi.org/10.1093/nar/gkr466