Recent advances in the discovery and combinatorial biosynthesis of microbial 14-membered macrolides and macrolactones

  • Je Won Park
  • Yeo Joon YoonEmail author
Metabolic Engineering and Synthetic Biology - Original Paper


Macrolides, especially 14-membered macrolides, are a valuable group of antibiotics that originate from various microorganisms. In addition to their antibacterial activity, newly discovered 14-membered macrolides exhibit other therapeutic potentials, such as anti-proliferative and anti-protistal activities. Combinatorial biosynthetic approaches will allow us to create structurally diversified macrolide analogs, which are especially important during the emerging post-antibiotic era. This review focuses on recent advances in the discovery of new 14-membered macrolides (also including macrolactones) from microorganisms and the current status of combinatorial biosynthetic approaches, including polyketide synthase (PKS) and post-PKS tailoring pathways, and metabolic engineering for improved production together with heterologous production of 14-membered macrolides.


14-Membered macrolide Polyketide synthase Post-polyketide synthase tailoring Combinatorial biosynthesis 



This work was supported by a National Research Foundation of Korea grant (2016R1A2A1A05005078) (Y.J.Y.) funded by the Ministry of Science and ICT, the High Value-Added Food Technology Development Program funded by the Ministry of Agriculture, Food, and Rural Affairs (114019052SB010) (Y.J.Y.), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health and Welfare (HI18C1664) (Y.J.Y.), the Collaborative Genome Program of the Korea Institute of Marine Science and Technology Promotion (KIMST) funded by the Ministry of Oceans and Fisheries (MOF) (No.20180430) (Y.J.Y.), and the Cooperative Research Program for Agriculture Science and Technology Development (PJ01317901) (J.W.P.) funded by the Rural Development Administration, Republic of Korea.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.


  1. 1.
    Akey DL, Gehret JJ, Khare D, Smith JL (2012) Insights from the sea: structural biology of marine polyketide synthases. Nat Prod Rep 29:1038–1049. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Alt S, Wilkinson B (2015) Biosynthesis of the novel macrolide antibiotic anthracimycin. ACS Chem Biol 10:2468–2479. CrossRefPubMedGoogle Scholar
  3. 3.
    Bauer J, Vine M, Coric I, Bosnar M, Pasalic I, Turkalj G, Lazarevski G, Culic O, Kragol G (2012) Impact of stereochemistry on the biological activity of novel oleandomycin derivatives. Bioorg Med Chem 20:2274–2281. CrossRefPubMedGoogle Scholar
  4. 4.
    Bayly CL, Yadav VG (2017) Towards precision engineering of canonical polyketide synthase domains: recent advances and future prospects. Molecules. CrossRefPubMedGoogle Scholar
  5. 5.
    Brockmann H, Henkel W (1951) Pikromycin, ein bitter schmeckendes antibioticum aus actinomyeceten. Chem Ber 84:284–288CrossRefGoogle Scholar
  6. 6.
    Cane DE (2010) Programming of erythromycin biosynthesis by a modular polyketide synthase. J Biol Chem 285:27517–27523. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chen C, Hong M, Chu J, Huang M, Ouyang L, Tian X, Zhuang Y (2017) Blocking the flow of propionate into TCA cycle through a mutB knockout leads to a significant increase of erythromycin production by an industrial strain of Saccharopolyspora erythraea. Bioprocess Biosyst Eng 40:201–209. CrossRefPubMedGoogle Scholar
  8. 8.
    Cipcic Paljetak H, Verbanac D, Padovan J, Dominis-Kramaric M, Kelneric Z, Peric M, Banjanac M, Ergovic G, Simon N, Broskey J, Holmes DJ, Erakovic Haber V (2016) Macrolones are a novel class of macrolide antibiotics active against key resistant respiratory pathogens in vitro and in vivo. Antimicrob Agents Chemother 60:5337–5348. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cyphert EL, Wallat JD, Pokorski JK, von Recum HA (2017) Erythromycin modification that improves its acidic stability while optimizing it for local drug delivery. Antibiotics. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dinos GP (2017) The macrolide antibiotic renaissance. Br J Pharmacol 174:2967–2983. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Eng CH, Backman TWH, Bailey CB, Magnan C, Garcia Martin H, Katz L, Baldi P, Keasling JD (2018) ClusterCAD: a computational platform for type I modular polyketide synthase design. Nucleic Acids Res 46:D509–D515. CrossRefPubMedGoogle Scholar
  12. 12.
    Fajdetic A, Cipcic Paljetak H, Lazarevski G, Hutinec A, Alihodzic S, Derek M, Stimac V, Andreotti D, Sunjic V, Berge JM, Mutak S, Dumic M, Lociuro S, Holmes DJ, Marsic N, Erakovic Haber V, Spaventi R (2010) 4′’-O-(omega-quinolylamino-alkylamino)propionyl derivatives of selected macrolides with the activity against the key erythromycin resistant respiratory pathogens. Bioorg Med Chem 18:6559–6568. CrossRefPubMedGoogle Scholar
  13. 13.
    Fang L, Guell M, Church GM, Pfeifer BA (2018) Heterologous erythromycin production across strain and plasmid construction. Biotechnol Prog 34:271–276. CrossRefPubMedGoogle Scholar
  14. 14.
    Fayed B, Ashford DA, Hashem AM, Amin MA, El Gazayerly ON, Gregory MA, Smith MC (2015) Multiplexed integrating plasmids for engineering of the erythromycin gene cluster for expression in Streptomyces spp. and combinatorial biosynthesis. Appl Environ Microbiol 81:8402–8413. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fernandes P, Martens E, Pereira D (2017) Nature nurtures the design of new semi-synthetic macrolide antibiotics. J Antibiot 70:527–533. CrossRefPubMedGoogle Scholar
  16. 16.
    Fu C, Auerbach D, Li Y, Scheid U, Luxenburger E, Garcia R, Irschik H, Müller R (2017) Solving the Puzzle of one-carbon loss in ripostatin biosynthesis. Angew Chem Int Ed Engl 56:2192–2197. CrossRefPubMedGoogle Scholar
  17. 17.
    Glaus F, Altmann KH (2013) Total synthesis of the myxobacterial macrolide ripostatin B. Chimia 67:227–230CrossRefGoogle Scholar
  18. 18.
    Harvey CJ, Puglisi JD, Pande VS, Cane DE, Khosla C (2012) Precursor directed biosynthesis of an orthogonally functional erythromycin analogue: selectivity in the ribosome macrolide binding pocket. J Am Chem Soc 134:12259–12265. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hayashi T, Yamashita T, Okada H, Oishi N, Sunagozaka H, Nio K, Hayashi T, Hara Y, Asahina Y, Yoshida M, Hashiba T, Suda T, Shirasaki T, Igarashi Y, Miyanouchi K, Yamashita T, Honda M, Kaneko S (2017) A novel mTOR inhibitor; anthracimycin for the treatment of human hepatocellular carcinoma. Anticancer Res 37:3397–3403. CrossRefPubMedGoogle Scholar
  20. 20.
    Held J, Gebru T, Kalesse M, Jansen R, Gerth K, Müller R, Mordmuller B (2014) Antimalarial activity of the myxobacterial macrolide chlorotonil A. Antimicrob Agents Chemother 58:6378–6384. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hugel HM, Smith AT, Rizzacasa MA (2016) Macrolactam analogues of macrolide natural products. Org Biomol Chem 14:11301–11316. CrossRefPubMedGoogle Scholar
  22. 22.
    Jang KH, Nam SJ, Locke JB, Kauffman CA, Beatty DS, Paul LA, Fenical W (2013) Anthracimycin, a potent anthrax antibiotic from a marine-derived actinomycete. Angew Chem Int Ed Engl 52:7822–7824. CrossRefPubMedGoogle Scholar
  23. 23.
    Jelic D, Antolovic R (2016) From erythromycin to azithromycin and new potential ribosome-binding antimicrobials. Antibiotics. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jiang M, Pfeifer BA (2013) Metabolic and pathway engineering to influence native and altered erythromycin production through E. coli. Metab Eng 19:42–49. CrossRefPubMedGoogle Scholar
  25. 25.
    Jiang M, Fang L, Pfeifer BA (2013) Improved heterologous erythromycin A production through expression plasmid re-design. Biotechnol Prog 29:862–869. CrossRefPubMedGoogle Scholar
  26. 26.
    Jiang M, Zhang H, Park SH, Li Y, Pfeifer BA (2013) Deoxysugar pathway interchange for erythromycin analogues heterologously produced through Escherichia coli. Metab Eng 20:92–100. CrossRefPubMedGoogle Scholar
  27. 27.
    Jungmann K, Jansen R, Gerth K, Huch V, Krug D, Fenical W, Müller R (2015) Two of a kind—the biosynthetic pathways of chlorotonil and anthracimycin. ACS Chem Biol 10:2480–2490. CrossRefPubMedGoogle Scholar
  28. 28.
    Kalkreuter E, Williams GJ (2018) Engineering enzymatic assembly lines for the production of new antimicrobials. Curr Opin Microbiol 45:140–148. CrossRefPubMedGoogle Scholar
  29. 29.
    Kang HS, Krunic A, Orjala J (2012) Sanctolide A, a 14-membered PK–NRP hybrid macrolide from the cultured cyanobacterium Oscillatoria sancta (SAG 74.79). Tetrahedron Lett 53:3563–3567. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kannan K, Kanabar P, Schryer D, Florin T, Oh E, Bahroos N, Tenson T, Weissman JS, Mankin AS (2014) The general mode of translation inhibition by macrolide antibiotics. Proc Natl Acad Sci USA 111:15958–15963. CrossRefPubMedGoogle Scholar
  31. 31.
    Karki S, Kwon SY, Yoo HG, Suh JW, Park SH, Kwon HJ (2010) The methoxymalonyl-acyl carrier protein biosynthesis locus and the nearby gene with the beta-ketoacyl synthase domain are involved in the biosynthesis of galbonolides in Streptomyces galbus, but these loci are separate from the modular polyketide synthase gene cluster. FEMS Microbiol Lett 310:69–75. CrossRefPubMedGoogle Scholar
  32. 32.
    Keatinge-Clay AT (2017) Polyketide synthase modules redefined. Angew Chem Int Ed Engl 56:4658–4660. CrossRefPubMedGoogle Scholar
  33. 33.
    Kim E, Moore BS, Yoon YJ (2015) Reinvigorating natural product combinatorial biosynthesis with synthetic biology. Nat Chem Biol 11:649–659. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kirm B, Magdevska V, Tome M, Horvat M, Karnicar K, Petek M, Vidmar R, Baebler S, Jamnik P, Fujs S, Horvat J, Fonovic M, Turk B, Gruden K, Petkovic H, Kosec G (2013) SACE_5599, a putative regulatory protein, is involved in morphological differentiation and erythromycin production in Saccharopolyspora erythraea. Microb Cell Fact 12:126. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Klaus M, Grininger M (2018) Engineering strategies for rational polyketide synthase design. Nat Prod Rep. CrossRefPubMedGoogle Scholar
  36. 36.
    Koryakina I, McArthur JB, Draelos MM, Williams GJ (2013) Promiscuity of a modular polyketide synthase towards natural and non-natural extender units. Org Biomol Chem 11:4449–4458. CrossRefPubMedGoogle Scholar
  37. 37.
    Koryakina I, Kasey C, McArthur JB, Lowell AN, Chemler JA, Li S, Hansen DA, Sherman DH, Williams GJ (2017) Inversion of extender unit selectivity in the erythromycin polyketide synthase by acyltransferase domain engineering. ACS Chem Biol 12:114–123. CrossRefPubMedGoogle Scholar
  38. 38.
    Lecomte N, Njardarson JT, Nagorny P, Yang G, Downey R, Ouerfelli O, Moore MA, Danishefsky SJ (2011) Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin. Proc Natl Acad Sci USA 108:15074–15078. CrossRefPubMedGoogle Scholar
  39. 39.
    LeTourneau N, Vimal P, Klepacki D, Mankin A, Melman A (2012) Synthesis and antibacterial activity of desosamine-modified macrolide derivatives. Bioorg Med Chem Lett 22:4575–4578. CrossRefPubMedGoogle Scholar
  40. 40.
    Liang JH, Han X (2013) Structure-activity relationships and mechanism of action of macrolides derived from erythromycin as antibacterial agents. Curr Top Med Chem 13:3131–3164CrossRefGoogle Scholar
  41. 41.
    Liu J, Chen Y, Wang W, Ren M, Wu P, Wang Y, Li C, Zhang L, Wu H, Weaver DT, Zhang B (2017) Engineering of an Lrp family regulator SACE_Lrp improves erythromycin production in Saccharopolyspora erythraea. Metab Eng 39:29–37. CrossRefPubMedGoogle Scholar
  42. 42.
    Ma S, Jiao B, Ju Y, Zheng M, Ma R, Liu L, Zhang L, Shen X, Ma C, Meng Y, Wang H, Qi Y, Ma X, Cui W (2011) Synthesis and antibacterial evaluation of novel clarithromycin derivatives with C-4′′ elongated arylalkyl groups against macrolide-resistant strains. Eur J Med Chem 46:556–566. CrossRefPubMedGoogle Scholar
  43. 43.
    Magee TV, Han S, McCurdy SP, Nguyen TT, Granskog K, Marr ES, Maguire BA, Huband MD, Chen JM, Subashi TA, Shanmugasundaram V (2013) Novel 3-O-carbamoyl erythromycin A derivatives (carbamolides) with activity against resistant staphylococcal and streptococcal isolates. Bioorg Med Chem Lett 23:1727–1731. CrossRefPubMedGoogle Scholar
  44. 44.
    McQuire JM, Bunch RL, Anderson RC, Boaz HE, Flynn EH, Powell HM, Smith JW (1952) Ilotycin, a new antibiotic. Antibiot Chemother 2:281–283Google Scholar
  45. 45.
    Park SR, Han AR, Ban YH, Yoo YJ, Kim EJ, Yoon YJ (2010) Genetic engineering of macrolide biosynthesis: past advances, current state, and future prospects. Appl Microbiol Biotechnol 85:1227–1239. CrossRefPubMedGoogle Scholar
  46. 46.
    Pavlovic D, Mutak S, Andreotti D, Biondi S, Cardullo F, Paio A, Piga E, Donati D, Lociuro S (2014) Synthesis and structure-activity relationships of alpha-amino-gamma-lactone ketolides: a novel class of macrolide antibiotics. ACS Med Chem Lett 5:1133–1137. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Pawlowski AC, Stogios PJ, Koteva K, Skarina T, Evdokimova E, Savchenko A, Wright GD (2018) The evolution of substrate discrimination in macrolide antibiotic resistance enzymes. Nat Commun 9:112. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pham CD, Hartmann R, Bohler P, Stork B, Wesselborg S, Lin W, Lai D, Proksch P (2014) Callyspongiolide, a cytotoxic macrolide from the marine sponge Callyspongia sp. Org Lett 16:266–269. CrossRefPubMedGoogle Scholar
  49. 49.
    Pignatello R, Simerska P, Leonardi A, Abdelrahim AS, Petronio GP, Fuochi V, Furneri PM, Ruozi B, Toth I (2016) Synthesis, characterization and in vitro evaluation of amphiphilic ion pairs of erythromycin and kanamycin antibiotics with liposaccharides. Eur J Med Chem 120:329–337. CrossRefPubMedGoogle Scholar
  50. 50.
    Ray L, Moore BS (2016) Recent advances in the biosynthesis of unusual polyketide synthase substrates. Nat Prod Rep 33:150–161. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Seiple IB, Zhang Z, Jakubec P, Langlois-Mercier A, Wright PM, Hog DT, Yabu K, Allu SR, Fukuzaki T, Carlsen PN, Kitamura Y, Zhou X, Condakes ML, Szczypinski FT, Green WD, Myers AG (2016) A platform for the discovery of new macrolide antibiotics. Nature 533:338–345. CrossRefPubMedGoogle Scholar
  52. 52.
    Scaglione JB, Akey DL, Sullivan R, Kittendorf JD, Rath CM, Kim ES, Smith JL, Sherman DH (2010) Biochemical and structural characterization of the tautomycetin thioesterase: analysis of a stereoselective polyketide hydrolase. Angew Chem Int Ed Engl 49:5726–5730. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Sundermann U, Bravo-Rodriguez K, Klopries S, Kushnir S, Gomez H, Sanchez-Garcia E, Schulz F (2013) Enzyme-directed mutasynthesis: a combined experimental and theoretical approach to substrate recognition of a polyketide synthase. ACS Chem Biol 8:443–450. CrossRefPubMedGoogle Scholar
  54. 54.
    Svetlov MS, Vazquez-Laslop N, Mankin AS (2017) Kinetics of drug-ribosome interactions defines the cidality of macrolide antibiotics. Proc Natl Acad Sci U S A 114:13673–13678. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Tang W, Prusov EV (2012) Total synthesis of RNA-polymerase inhibitor ripostatin B and 15-deoxyripostatin A. Angew Chem Int Ed Engl 51:3401–3404. CrossRefPubMedGoogle Scholar
  56. 56.
    Tripathi A, Choi SS, Sherman DH, Kim ES (2016) Thioesterase domain swapping of a linear polyketide tautomycetin with a macrocyclic polyketide pikromycin in Streptomyces sp. CK4412. J Ind Microbiol Biotechnol 43:1189–1193. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Valenzano CR, You YO, Garg A, Keatinge-Clay A, Khosla C, Cane DE (2010) Stereospecificity of the dehydratase domain of the erythromycin polyketide synthase. J Am Chem Soc 132:14697–14699. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Velvadapu V, Glassford I, Lee M, Paul T, Debrosse C, Klepacki D, Small MC, Mackerell AD Jr, Andrade RB (2012) Desmethyl macrolides: synthesis and evaluation of 4,10-didesmethyl telithromycin. ACS Med Chem Lett 3:211–215. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Wong FT, Khosla C (2012) Combinatorial biosynthesis of polyketides—a perspective. Curr Opin Chem Biol 16:117–123. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Wu J, Zhang Q, Deng W, Qian J, Zhang S, Liu W (2011) Toward improvement of erythromycin A production in an industrial Saccharopolyspora erythraea strain via facilitation of genetic manipulation with an artificial attB site for specific recombination. Appl Environ Microbiol 77:7508–7516. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Wu P, Pan H, Zhang C, Wu H, Yuan L, Huang X, Zhou Y, Ye BC, Weaver DT, Zhang L, Zhang B (2014) SACE_3986, a TetR family transcriptional regulator, negatively controls erythromycin biosynthesis in Saccharopolyspora erythraea. J Ind Microbiol Biotechnol 41:1159–1167. CrossRefPubMedGoogle Scholar
  62. 62.
    Wu H, Chen M, Mao Y, Li W, Liu J, Huang X, Zhou Y, Ye BC, Zhang L, Weaver DT, Zhang B (2014) Dissecting and engineering of the TetR family regulator SACE_7301 for enhanced erythromycin production in Saccharopolyspora erythraea. Microb Cell Fact 13:158. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Ying L, Tang D (2010) Recent advances in the medicinal chemistry of novel erythromycin-derivatized antibiotics. Curr Top Med Chem 10:1441–1469CrossRefGoogle Scholar
  64. 64.
    Yuzawa S, Deng K, Wang G, Baidoo EE, Northen TR, Adams PD, Katz L, Keasling JD (2017) Comprehensive in vitro analysis of acyltransferase domain exchanges in modular polyketide synthases and its application for short-chain ketone production. ACS Synth Biol 6:139–147. CrossRefPubMedGoogle Scholar
  65. 65.
    Yuzawa S, Backman TWH, Keasling JD, Katz L (2018) Synthetic biology of polyketide synthases. J Ind Microbiol Biotechnol 45:621–633. CrossRefPubMedGoogle Scholar
  66. 66.
    Zhang H, Wang Y, Wu J, Skalina K, Pfeifer BA (2010) Complete biosynthesis of erythromycin A and designed analogs using E. coli as a heterologous host. Chem Biol 17:1232–1240. CrossRefPubMedGoogle Scholar
  67. 67.
    Zhang L, Jiao B, Yang X, Liu L, Ma S (2011) Synthesis and antibacterial activity of new 4′′-O-carbamates of 11,12-cyclic carbonate erythromycin A 6,9-imino ether. J Antibiot 64:243–247. CrossRefPubMedGoogle Scholar
  68. 68.
    Zhang Q, Wu J, Qian J, Chu J, Zhuang Y, Zhang S, Liu W (2011) Knocking out of tailoring genes eryK and eryG in an industrial erythromycin-producing strain of Saccharopolyspora erythraea leading to overproduction of erythromycin B, C and D at different conversion ratios. Lett Appl Microbiol 52:129–137. CrossRefPubMedGoogle Scholar
  69. 69.
    Zhang H, Skalina K, Jiang M, Pfeifer BA (2012) Improved E. coli erythromycin A production through the application of metabolic and bioprocess engineering. Biotechnol Prog 28:292–296. CrossRefPubMedGoogle Scholar
  70. 70.
    Zhang G, Li Y, Fang L, Pfeifer BA (2015) Tailoring pathway modularity in the biosynthesis of erythromycin analogs heterologously engineered in E. coli. Sci Adv 1:500077. CrossRefGoogle Scholar

Copyright information

© Society for Industrial Microbiology and Biotechnology 2018

Authors and Affiliations

  1. 1.School of Biosystem and Biomedical ScienceKorea UniversitySeoulRepublic of Korea
  2. 2.Department of Chemistry and NanoscienceEwha Womans UniversitySeoulRepublic of Korea

Personalised recommendations