Resistance and Phylogeny Guided Discovery Reveals Structural Novelty of Tetracycline Antibiotics

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 Dec 15

PMID 36519048

Authors

Ling Yu Li

Yi Ling Hu

Jia Lin Sun

Long Bo Yu

Jing Shi

Zi Ru Wang

Zhi Kai Guo

Bo Zhang

Wen Jie Guo

Ren Xiang Tan

Hui Ming Ge

Affiliations

Soon will be listed here.

Abstract

Tetracyclines are a class of antibiotics that exhibited potent activity against a wide range of Gram-positive and Gram-negative bacteria, yet only five members were isolated from actinobacteria, with two of them approved as clinical drugs. In this work, we developed a genome mining strategy using a TetR/MarR-transporter, a pair of common resistance enzymes in tetracycline biosynthesis, as probes to find the potential tetracycline gene clusters in the actinobacteria genome database. Further refinement using the phylogenetic analysis of chain length factors resulted in the discovery of 25 distinct tetracycline gene clusters, which finally resulted in the isolation and characterization of a novel tetracycline, hainancycline (1). Through genetic and biochemical studies, we elucidated the biosynthetic pathway of 1, which involves a complex glycosylation process. Our work discloses nature's huge capacity to generate diverse tetracyclines and expands the chemical diversity of tetracyclines.

Citing Articles

Newly Discovered Mechanisms of Antibiotic Self-Resistance with Multiple Enzymes Acting at Different Locations and Stages.

Chen X, Pan H, Tang G Antibiotics (Basel). 2023; 12(1).

PMID: 36671236 PMC: 9854587. DOI: 10.3390/antibiotics12010035.

References

Bretschneider T, Zocher G, Unger M, Scherlach K, Stehle T, Hertweck C . A ketosynthase homolog uses malonyl units to form esters in cervimycin biosynthesis. Nat Chem Biol. 2011; 8(2):154-61. DOI: 10.1038/nchembio.746. View

Stevenson L, Bracegirdle J, Liu L, Sharrock A, Ackerley D, Keyzers R . Metathramycin, a new bioactive aureolic acid discovered by heterologous expression of a metagenome derived biosynthetic pathway. RSC Chem Biol. 2021; 2(2):556-567. PMC: 8341913. DOI: 10.1039/d0cb00228c. View

Blair J, Webber M, Baylay A, Ogbolu D, Piddock L . Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 2014; 13(1):42-51. DOI: 10.1038/nrmicro3380. View

Perez M, Lombo F, Zhu L, Gibson M, Brana A, Rohr J . Combining sugar biosynthesis genes for the generation of L- and D-amicetose and formation of two novel antitumor tetracenomycins. Chem Commun (Camb). 2005; (12):1604-6. DOI: 10.1039/b417815g. View

Hoffmeister D, Ichinose K, Domann S, Faust B, Trefzer A, Drager G . The NDP-sugar co-substrate concentration and the enzyme expression level influence the substrate specificity of glycosyltransferases: cloning and characterization of deoxysugar biosynthetic genes of the urdamycin biosynthetic gene cluster. Chem Biol. 2000; 7(11):821-31. DOI: 10.1016/s1074-5521(00)00029-6. View

Feng Z, Kallifidas D, Brady S . Functional analysis of environmental DNA-derived type II polyketide synthases reveals structurally diverse secondary metabolites. Proc Natl Acad Sci U S A. 2011; 108(31):12629-34. PMC: 3150919. DOI: 10.1073/pnas.1103921108. View

Shi J, Liu C, Zhang B, Guo W, Zhu J, Chang C . Genome mining and biosynthesis of kitacinnamycins as a STING activator. Chem Sci. 2019; 10(18):4839-4846. PMC: 6510318. DOI: 10.1039/c9sc00815b. View

Rudolf J, Yan X, Shen B . Genome neighborhood network reveals insights into enediyne biosynthesis and facilitates prediction and prioritization for discovery. J Ind Microbiol Biotechnol. 2015; 43(2-3):261-76. PMC: 4753101. DOI: 10.1007/s10295-015-1671-0. View

Guilfoile P, Hutchinson C . The Streptomyces glaucescens TcmR protein represses transcription of the divergently oriented tcmR and tcmA genes by binding to an intergenic operator region. J Bacteriol. 1992; 174(11):3659-66. PMC: 206055. DOI: 10.1128/jb.174.11.3659-3666.1992. View

10.

Hertweck C, Luzhetskyy A, Rebets Y, Bechthold A . Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork. Nat Prod Rep. 2007; 24(1):162-90. DOI: 10.1039/b507395m. View

11.

Duggar B . Aureomycin; a product of the continuing search for new antibiotics. Ann N Y Acad Sci. 1948; 51(Art. 2):177-81. DOI: 10.1111/j.1749-6632.1948.tb27262.x. View

12.

Jia X, Tian Z, Shao L, Qu X, Zhao Q, Tang J . Genetic characterization of the chlorothricin gene cluster as a model for spirotetronate antibiotic biosynthesis. Chem Biol. 2006; 13(6):575-85. DOI: 10.1016/j.chembiol.2006.03.008. View

13.

Nelson M, Levy S . The history of the tetracyclines. Ann N Y Acad Sci. 2011; 1241:17-32. DOI: 10.1111/j.1749-6632.2011.06354.x. View

14.

Lukezic T, Lesnik U, Podgorsek A, Horvat J, Polak T, Sala M . Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea: a platform for producing novel tetracycline antibiotics. Microbiology (Reading). 2013; 159(Pt 12):2524-2532. DOI: 10.1099/mic.0.070995-0. View

15.

Moller T, Overgaard M, Nielsen S, Bortolaia V, Sommer M, Guardabassi L . Relation between tetR and tetA expression in tetracycline resistant Escherichia coli. BMC Microbiol. 2016; 16:39. PMC: 4788846. DOI: 10.1186/s12866-016-0649-z. View

16.

Mitscher L, Juvarkar J, Rosenbrook Jr W, ANDRES W, Schenk J, Egan R . Structure of chelocardin, a novel tetracycline antibiotic. J Am Chem Soc. 1970; 92(20):6070-1. DOI: 10.1021/ja00723a049. View

17.

Fuoco D . Classification Framework and Chemical Biology of Tetracycline-Structure-Based Drugs. Antibiotics (Basel). 2016; 1(1):1-13. PMC: 4790241. DOI: 10.3390/antibiotics1010001. View

18.

Ramos J, Martinez-Bueno M, Molina-Henares A, Teran W, Watanabe K, Zhang X . The TetR family of transcriptional repressors. Microbiol Mol Biol Rev. 2005; 69(2):326-56. PMC: 1197418. DOI: 10.1128/MMBR.69.2.326-356.2005. View

19.

Pickens L, Kim W, Wang P, Zhou H, Watanabe K, Gomi S . Biochemical analysis of the biosynthetic pathway of an anticancer tetracycline SF2575. J Am Chem Soc. 2009; 131(48):17677-89. PMC: 2800175. DOI: 10.1021/ja907852c. View

20.

Thaker M, Spanogiannopoulos P, Wright G . The tetracycline resistome. Cell Mol Life Sci. 2009; 67(3):419-31. PMC: 11115633. DOI: 10.1007/s00018-009-0172-6. View