Thursday, June 25, 2026
No menu items!
HomeNatureA Streptomyces megacluster encodes synergistic biotin-targeting antibiotics

A Streptomyces megacluster encodes synergistic biotin-targeting antibiotics

  • Wiebach, V. et al. The anti-staphylococcal lipolanthines are ribosomally synthesized lipopeptides. Nat. Chem. Biol. 14, 652–654 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kayrouz, C. M., Zhang, Y., Pham, T. M. & Ju, K. S. Genome mining reveals the phosphonoalamide natural products and a new route in phosphonic acid biosynthesis. ACS Chem. Biol. 15, 1921–1929 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tang, X. et al. Identification of thiotetronic acid antibiotic biosynthetic pathways by target-directed genome mining. ACS Chem. Biol. 10, 2841–2849 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Culp, E. J. et al. Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling. Nature 578, 582–587 (2020).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Culp, E. J. et al. ClpP inhibitors are produced by a widespread family of bacterial gene clusters. Nat. Microbiol. 7, 451–462 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, C. et al. Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster. Proc. Natl Acad. Sci. USA 119, e2117941119 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morshed, M. T. et al. Chlorinated metabolites from Streptomyces sp. highlight the role of biosynthetic mosaics and superclusters in the evolution of chemical diversity. Org. Biomol. Chem. 19, 6147–6159 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Meyer, K. J. & Nodwell, J. R. Biology and applications of co-produced, synergistic antimicrobials from environmental bacteria. Nat. Microbiol. 6, 1118–1128 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, X. & Li, B. Analysis of co-localized biosynthetic gene clusters identifies a membrane-permeabilizing natural product. J. Nat. Prod. 87, 1694–1703 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alanjary, M. & Medema, M. H. Mining bacterial genomes to reveal secret synergy. J. Biol. Chem. 293, 19996–19997 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mrak, P. et al. Discovery of the actinoplanic acid pathway in Streptomyces rapamycinicus reveals a genetically conserved synergism with rapamycin. J. Biol. Chem. 293, 19982–19995 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Padhi, C. et al. Metagenomic study of lake microbial mats reveals protease-inhibiting antiviral peptides from a core microbiome member. Proc. Natl Acad. Sci. USA 121, e2409026121 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brown, E. D. & Wright, G. D. Antibacterial drug discovery in the resistance era. Nature 529, 336–343 (2016).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 83, 770–803 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Atanasov, A. G., Zotchev, S. B., Dirsch, V. M., International Natural Product Sciences Taskforce & Supuran, C. T. Natural products in drug discovery: advances and opportunities. Nat. Rev. Drug Discov. 20, 200–216 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mann, S. et al. Inhibition of diamino pelargonic acid aminotransferase, an enzyme of the biotin biosynthetic pathway, by amiclenomycin: a mechanistic study. Helv. Chim. Acta 86, 3836–3850 (2003).

    Article 
    CAS 

    Google Scholar
     

  • Poetsch, M., Zahner, H., Werner, R. G., Kern, A. & Jung, G. Metabolic products from microorganisms. 230. Amiclenomycin-peptides, new antimetabolites of biotin. Taxonomy, fermentation and biological properties. J. Antibiot. 38, 312–320 (1985).

    Article 
    CAS 

    Google Scholar
     

  • Bockman, M. R. et al. Investigation of (S)-(–)-acidomycin: a selective antimycobacterial natural product that inhibits biotin synthase. ACS Infect. Dis. 5, 598–617 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qu, D. et al. Mycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin. Nat. Commun. 15, 4161 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reissier, S. & Cattoir, V. Streptogramins for the treatment of infections caused by Gram-positive pathogens. Expert Rev. Anti Infect. Ther. 19, 587–599 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Drawz, S. M. & Bonomo, R. A. Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev. 23, 160–201 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zlitni, S., Ferruccio, L. F. & Brown, E. D. Metabolic suppression identifies new antibacterial inhibitors under nutrient limitation. Nat. Chem. Biol. 9, 796–804 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gehrke, S. S. et al. Exploiting the sensitivity of nutrient transporter deletion strains in discovery of natural product antimetabolites. ACS Infect. Dis. 3, 955–965 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Carfrae, L. A. et al. Mimicking the human environment in mice reveals that inhibiting biotin biosynthesis is effective against antibiotic-resistant pathogens. Nat. Microbiol. 5, 93–101 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Montaser, R. & Kelleher, N. L. Discovery of the biosynthetic machinery for stravidins, biotin antimetabolites. ACS Chem. Biol. 15, 1134–1140 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blin, K. et al. antiSMASH 7.0: new and improved predictions for detection, regulation, chemical structures and visualisation. Nucleic Acids Res. 51, W46–W50 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baltz, R. H. Marcel Faber Roundtable: is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration? J. Ind. Microbiol. Biotechnol. 33, 507–513 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xu, M. et al. GPAHex—a synthetic biology platform for type IV-V glycopeptide antibiotic production and discovery. Nat. Commun. 11, 5232 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, J. J., Yamanaka, K., Tang, X. & Moore, B. S. Direct cloning and heterologous expression of natural product biosynthetic gene clusters by transformation-associated recombination. Methods Enzymol. 621, 87–110 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bibb, M. J., White, J., Ward, J. M. & Janssen, G. R. The mRNA for the 23S rRNA methylase encoded by the ermE gene of Saccharopolyspora erythraea is translated in the absence of a conventional ribosome-binding site. Mol. Microbiol. 14, 533–545 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gomez-Escribano, J. P. & Bibb, M. J. Engineering Streptomyces coelicolor for heterologous expression of secondary metabolite gene clusters. Microb. Biotechnol. 4, 207–215 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Grundy, W. E. et al. Actithiazic acid. I. Microbiological studies. Antibiot. Chemother. 2, 399–408 (1952).

    CAS 

    Google Scholar
     

  • Datsenko, K. A. & Wanner, B. L. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl Acad. Sci. USA 97, 6640–6645 (2000).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, H., Bu, J. & Liu, H.-W. Radical S-adenosylmethionine sulfurtransferase MybB-catalysed formation of the 4-thiazolidinone core in mycobacidin represents an intersection between primary and secondary metabolism. J. Am. Chem. Soc. 147, 4180–4187 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sirithanakorn, C. & Cronan, J. E. Biotin, a universal and essential cofactor: synthesis, ligation and regulation. FEMS Microbiol. Rev. 45, fuab003 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Parnas, B. L. et al. Isolation and structure of leukotriene-A4 hydrolase inhibitor: 8(S)-amino-2(R)-methyl-7-oxononanoic acid produced by Streptomyces diastaticus. J. Nat. Prod. 59, 962–964 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cronan, J. E. Jr. The E. coli bio operon: transcriptional repression by an essential protein modification enzyme. Cell 58, 427–429 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chapman-Smith, A., Morris, T. W., Wallace, J. C. & Cronan, J. E. Jr. Molecular recognition in a post-translational modification of exceptional specificity. Mutants of the biotinylated domain of acetyl-CoA carboxylase defective in recognition by biotin protein ligase. J. Biol. Chem. 274, 1449–1457 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kitahara, T., Hotta, K., Yoshida, M. & Okami, Y. Biological studies of amiclenomycin. J. Antibiot. 28, 215–221 (1975).

    Article 
    CAS 

    Google Scholar
     

  • Fu, J. et al. The two-component system CepRS regulates the cephamycin C biosynthesis in Streptomyces clavuligerus F613-1. AMB Express 9, 118 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Challis, G. L. & Hopwood, D. A. Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc. Natl Acad. Sci. USA 100, 14555–14561 (2003).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kurosawa, S. et al. Streptavidins coordinate biotin sequestration and self-resistance within a biotin-pathway antibiotic network. Adv. Sci. (Weinh) https://doi.org/10.1002/advs.202523813 (2026).

  • Larionov, V., Kouprina, N., Solomon, G., Barrett, J. C. & Resnick, M. A. Direct isolation of human BRCA2 gene by transformation-associated recombination in yeast. Proc. Natl Acad. Sci. USA 94, 7384–7387 (1997).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Edgar, R. C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Capella-Gutiérrez, S., Silla-Martínez, J. M. & Gabaldón, T. trimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses. Bioinformatics 25, 1972–1973 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Minh, B. Q. et al. IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era. Mol. Biol. Evol. 37, 1530–1534 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Minh, B. Q., Nguyen, M. A. T. & von Haeseler, A. Ultrafast approximation for phylogenetic bootstrap. Mol. Biol. Evol. 30, 1188–1195 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Asnicar, F. et al. Precise phylogenetic analysis of microbial isolates and genomes from metagenomes using PhyloPhlAn 3.0. Nat. Commun. 11, 2500 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Revell, L. J. phytools 2.0: An updated R ecosystem for phylogenetic comparative methods (and other things). PeerJ 12, e16505 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • The pandas development team. pandas-dev/pandas: pandas (v2.2.2). Zenodo https://doi.org/10.5281/zenodo.10957263 (2024).

  • Cock, P. J. A. et al. Biopython: freely available Python tools for computational molecular biology and bioinformatics. Bioinformatics 25, 1422–1423 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cook, M. A. et al. Lessons from assembling a microbial natural product and pre-fractionated extract library in an academic laboratory. J. Ind. Microbiol. Biotechnol. 50, kuad042 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, M., Wang, W. & Wright, G. D. Glycopeptide antibiotic discovery in the genomic era. Methods Enzymol. 665, 325–346 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kieser, T., Bibb, M. J., Buttner, M. J., Chater, K. F. & Hopwood, D. A. Practical Streptomyces Genetics (John Innes Foundation, 2000).

  • Wang, W. et al. An engineered strong promoter for streptomycetes. Appl. Environ. Microbiol. 79, 4484–4492 (2013).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dong, J., Wei, J., Li, H., Zhao, S. & Guan, W. An efficient markerless deletion system suitable for the industrial strains of Streptomyces. J. Microbiol. Biotechnol. 31, 1722–1731 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zaslaver, A. et al. A comprehensive library of fluorescent transcriptional reporters for Escherichia coli. Nat. Methods 3, 623–628 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kitagawa, M. et al. Complete set of ORF clones of Escherichia coli ASKA library (a complete set of E. coli K-12 ORF archive): unique resources for biological research. DNA Res. 12, 291–299 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wilson, D. J. et al. A continuous fluorescence displacement assay for BioA: an enzyme involved in biotin biosynthesis. Anal. Biochem. 416, 27–38 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, Y. & Sousa, R. Novel system for in vivo biotinylation and its application to crab antimicrobial protein scygonadin. Biotechnol. Lett. 34, 1629–1635 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Broussard, T. C. et al. The three-dimensional structure of the biotin carboxylase-biotin carboxyl carrier protein complex of E. coli acetyl-CoA carboxylase. Structure 21, 650–657 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mann, S., Eveleigh, L., Lequin, O. & Ploux, O. A microplate fluorescence assay for DAPA aminotransferase by detection of the vicinal diamine 7,8-diaminopelargonic acid. Anal. Biochem. 432, 90–96 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kornberg, A. & Pricer, W. E. Jr. Enzymatic phosphorylation of adenosine and 2,6-diaminopurine riboside. J. Biol. Chem. 193, 481–495 (1951).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Marty, M. T. et al. Bayesian deconvolution of mass and ion mobility spectra: from binary interactions to polydisperse ensembles. Anal. Chem. 87, 4370–4376 (2015).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seeliger, J. C. et al. A riboswitch-based inducible gene expression system for mycobacteria. PLoS ONE 7, e29266 (2012).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Agarwal, N. & Tyagi, A. K. Mycobacterial transcriptional signals: requirements for recognition by RNA polymerase and optimal transcriptional activity. Nucleic Acids Res. 34, 4245–4257 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Andreu, N. et al. Optimisation of bioluminescent reporters for use with mycobacteria. PLoS ONE 5, e10777 (2010).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, MSB4100050 (2006).

    Article 

    Google Scholar
     

  • Cakić, N., Kopke, B., Rabus, R. & Wilkes, H. Suspect screening and targeted analysis of acyl coenzyme A thioesters in bacterial cultures using a high-resolution tribrid mass spectrometer. Anal. Bioanal. Chem. 413, 3599–3610 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hackenberger, D. Source code for: a ubiquitous Streptomyces biosynthetic megacluster encodes an arsenal of synergistic biotin-targeting antibiotics. Zenodo https://doi.org/10.5281/zenodo.19899453 (2026).

  • RELATED ARTICLES

    Most Popular

    Recent Comments