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STRUCTURE-BASED ANTIBIOTIC DESIGN

ESKAPE velocity: total synthesis platforms promise to increase the pace and diversity of antibiotic development

Nature Structural & Molecular Biology volume 29, pages 3–4 (2022)Cite this article

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Iboxamycin (IBX) is a new oxepanoprolinamide antibiotic based on clindamycin. Crystal structures of IBX in complex with bacterial ribosomes uncover the structural mechanism of its activity against multidrug-resistant pathogens and reveal key interactions with tRNAs and 23S rRNA, including resistance-conferring rRNA methylations.

Antibiotic resistance is a growing threat to public health. Drug-resistant microbial infections now result in 700,000 deaths per year globally and are projected to cause up to 10 million deaths annually by 2050 should no new antibiotics be identified1. Historically, the development of new antibiotic compounds has depended upon semisynthesis, whereby natural products are modified to yield new drugs2. However, semisynthesis presents challenges, particularly its limited ability to generate new chemical scaffolds. The development of new antibiotic compounds has slowed over the past few decades3,4, and there is little financial incentive for pharmaceutical companies to develop the next line of antibiotics. The growing clinical threat of antibiotic-resistant ‘ESKAPE’ pathogens5 (encompassing several pathogenic species from Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas and Enterobacter) combined with the limited number of new antibiotics has allowed the increasing spread of resistance. Specifically, some clinical strains have gained resistance to important antibiotics active against the large 50S ribosomal subunit, including the MLSB phenotype (resistance to macrolides, lincosamides and class B streptogramins) and PHLOPSA phenotype (resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins and class A streptogramins). Resistance is achieved through the expression of 23S ribosomal RNA (rRNA) methyltransferases from the Erm and Cfr families6,7,8.

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Fig. 1: New antibiotic IBX inhibits bacterial protein synthesis and appears to overcome resistance mechanisms.

References

  1. United Nations Interagency Coordination Group on Antimicrobial Resistance. No Time to Wait: Securing the Future from Drug-Resistant Infections (UN, 2019).

  2. Wright, P. M., Seiple, I. B. & Myers, A. G. Angew. Chem. Intl Edn. Engl. 53, 8840–8869 (2014).

    Article  CAS  Google Scholar 

  3. Simpkin, V. L., Renwick, M. J., Kelly, R. & Mossialos, E. J. Antibiot. 70, 1087–1096 (2017).

    Article  CAS  Google Scholar 

  4. Spellberg, B. Crit. Care 18, 228 (2014).

    Article  Google Scholar 

  5. Santajit, S. & Indrawattana, N. Mechanisms of Antimicrobial Resistance in ESKAPE. Pathogens. Biomed. Res. Intl. 2016, 2475067 (2016).

    Google Scholar 

  6. Long, K. S., Poehlsgaard, J., Kehrenberg, C., Schwarz, S. & Vester, B. Antimicrob. Agents Chemother. 50, 2500–2505 (2006).

    Article  CAS  Google Scholar 

  7. Smith, L. K. & Mankin, A. S. Antimicrob. Agents Chemother. 52, 1703–1712 (2008).

    Article  CAS  Google Scholar 

  8. Leclercq, R. Clin. Infect. Dis. 34, 482–492 (2002).

    Article  CAS  Google Scholar 

  9. Mitcheltree, M. J. et al. Nature https://doi.org/10.1038/s41586-021-04045-6 (2021).

  10. Seiple, I. B. et al. Nature 533, 338–345 (2016).

    Article  CAS  Google Scholar 

  11. Charest, M. G., Lerner, C. D., Brubaker, J. D., Siegel, D. R. & Myers, A. G. Science 308, 395–398 (2005).

    Article  CAS  Google Scholar 

  12. Li, Q. et al. Nature 586, 145–150 (2020).

    Article  CAS  Google Scholar 

  13. Spížek, J. & Řezanka, T. Biochem. Pharmacol. 133, 20–28 (2017).

    Article  Google Scholar 

  14. Tenson, T., Lovmar, M. & Ehrenberg, M. J. Mol. Biol. 330, 1005–1014 (2003).

    Article  CAS  Google Scholar 

  15. Marks, J. et al. Proc. Natl Acad. Sci. USA 113, 12150 (2016).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dunham lab members P. Srinivas and H.A. Nguyen for their comments. Research in the Dunham lab is funded by US National Institutes of Health grants GM093278, AI088025 and GM121650 and by the Burroughs Wellcome Fund (Investigator in the Pathogenesis of Infectious Diseases Awardee).

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Authors and Affiliations

  1. Graduate Program in Biochemistry, Cell and Developmental Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA

    Jacob M. Mattingly

  2. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA

    Jacob M. Mattingly & Christine M. Dunham

  3. Emory Antibiotic Resistance Center (ARC), Emory University, Atlanta, GA, USA

    Jacob M. Mattingly & Christine M. Dunham

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  1. Jacob M. Mattingly
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Correspondence to Christine M. Dunham.

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Mattingly, J.M., Dunham, C.M. ESKAPE velocity: total synthesis platforms promise to increase the pace and diversity of antibiotic development. Nat Struct Mol Biol 29, 3–4 (2022). https://doi.org/10.1038/s41594-021-00708-0

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