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Antibacterial and mechanism of action studies of boxazomycin A

Abstract

Boxazomycins A-C are potent broad-spectrum antibiotics isolated from Actinomycetes strain G495-1 in 1987. We now report that boxazomycin A inhibits bacterial growth by selectively inhibiting protein synthesis, its effect is bacteriostatic, and it is equally active against drug resistant bacterial strains. No cross-resistance to protein synthesis inhibitors was observed suggesting that its inhibition is distinct from clinical protein synthesis inhibitors. We also report in vivo efficacy in a Staphylococcus aureus murine infection model supported by corresponding pharmacokinetic studies.

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References

  1. Singh SB, Phillips JW, Wang J. Highly, sensitive target based whole cell antibacterial discovery strategy by antisense RNA silencing. Curr Opin Drug Discov Dev. 2007;10:160.

    CAS  Google Scholar 

  2. Zhang C, Occi J, Masurekar P, Barrett JF, Zink DL, Smith S, Onishi R, Ha S, Salazar O, Genilloud O, Basilio A, Vicente F, Gill C, Hickey EJ, Dorso K, Motyl M, Singh SB. Isolation, structure, and antibacterial activity of philipimycin, a thiazolyl peptide discovered from Actinoplanes philippinensis MA7347. J Am Chem Soc. 2008;130:12102.

    Article  CAS  PubMed  Google Scholar 

  3. Wang J, Soisson SM, Young K, Shoop W, Kodali S, Galgoci A, Painter R, Parthasarathy G, Tang Y, Cummings R, Ha S, Dorso K, Motyl M, Jayasuriya H, Ondeyka J, Herath K, Zhang C, Hernandez L, Alloco J, Basilio Á, Tormo JR, Genilloud O, Vicente F, Pelaez F, Colwell L, Lee SH, Michael B, Felcetto T, Gill C, Silver LL, Hermes J, Bartizal K, Barrett J, Schmatz D, Becker JW, Cully D, Singh SB. Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature. 2006;441:358.

    Article  CAS  PubMed  Google Scholar 

  4. Singh SB, Jayasuriya H, Ondeyka JG, Herath KB, Zhang C, Zink DL, Tsou NN, Ball RG, Basilio A, Genilloud O, Diez MT, Vicente F, Pelaez F, Young K, Wang J. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Jayasuriya H, Herath KB, Zhang C, Zink DL, Basilio A, Genilloud O, Diez MT, Vicente F, Gonzalez I, Salazar O, Pelaez F, Cummings R, Ha S, Wang J, Singh SB. Isolation and structure of platencin: a novel FabH and FabF dual inhibitor with potent broad spectrum antibiotic activity produced by Streptomyces platensis MA7339. Angew Chem Int Ed. 2007;46:4684.

    Article  CAS  Google Scholar 

  6. Wang J, Kodali S, Lee SH, Galgoci A, Painter R, Dorso K, Racine F, Motyl M, Hernandez L, Tinney E, Colletti S, Herath K, Cummings R, Salazar O, Gonzalez I, Basilio A, Vicente F, Genilloud O, Pelaez F, Jayasuriya H, Young K, Cully D, Singh SB. Platencin is a dual FabF and FabH inhibitor with potent in vivo antibiotic properties. Proc Natl Acad Sci (USA). 2007;104:7612.

    Article  CAS  PubMed  Google Scholar 

  7. Phillips JW, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, Salowe S, Wiltsie J, Allocco J, Sigmund J, Dorso K, Lee S, Skwish S, de la Cruz M, Martin J, Vicente F, Genilloud O, Lu J, Painter RE, Young K, Overbye K, Donald RG, Singh SB. Discovery of kibdelomycin, a potent new class of bacterial type II topoisomerase inhibitor by chemical-genetic profiling in Staphylococcus aureus. Chem Biol. 2011;18:955.

    Article  CAS  PubMed  Google Scholar 

  8. Singh SB, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, Salowe S, Wiltsie J, Allocco J, Sigmund J, Dorso K, de la Cruz M, Martin J, Vicente F, Genilloud O, Donald RG, Phillips JW. Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities. Bioorg Med Chem Lett. 2012;22:7127.

    Article  CAS  PubMed  Google Scholar 

  9. Lu J, Patel S, Sharma N, Soisson SM, Kishii R, Takei M, Fukuda Y, Lumb KJ, Singh SB. Structures of kibdelomycin bound to Staphylococcus aureus GyrB and ParE showed a novel U-shaped binding mode. ACS Chem Biol. 2014;9:2023.

    Article  CAS  PubMed  Google Scholar 

  10. Miesel L, Hecht DW, Osmolski JR, Gerding D, Flattery A, Li F, Lan J, Lipari P, Polishook JD, Liang L, Liu J, Olsen DB, Singh SB. Kibdelomycin is a potent and selective agent against toxigenic Clostridium difficile. Antimicrob Agents Chemother. 2014;58:2387.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Singh SB, Dayananth P, Balibar CJ, Garlisi CG, Lu J, Kishii R, Takei M, Fukuda Y, Ha S, Young K. Kibdelomycin is a bactericidal broad-spectrum aerobic antibacterial agent. Antimicrob Agents Chemother. 2015;59:3474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Singh SB. Discovery and development of kibdelomycin, a new class of broad-spectrum antibiotics targeting the clinically proven bacterial type II topoisomerase. Bioorg Med Chem. 2016;24:6291.

    Article  CAS  PubMed  Google Scholar 

  13. Saitoh, K; Konishi, M; Tomita, K, Boxazomycin A and B, new antibiotics containing benzoxazole nucleus, US 4,690,926, 1987.

  14. Kusumi T, Ooi T, Walchli MR, Kakisawa H. Structure of the novel antibiotics boxazomycins A, B, and C. J Am Chem Soc. 1988;110:2954.

    Article  CAS  Google Scholar 

  15. Suto MJ, Turner WR. Synthesis of Boxazomycin B and related analogs. Tetrahedron Lett. 1995;36:7213.

    Article  CAS  Google Scholar 

  16. Richardson C, Rewcastle GW, Hoyer D, Denny WA. Palladium-catalyzed cross-coupling in the synthesis of pyridinyl boxazomycin C analogues. J Org Chem. 2005;70:7436.

    Article  CAS  PubMed  Google Scholar 

  17. Šlachtová V, Brulíková L. Benzoxazole derivatives as promising antitubercular agents. ChemistrySelect. 2018;3:4653.

    Article  Google Scholar 

  18. Singh SB, Occi J, Jayasuriya H, Herath K, Motyl M, Dorso K, Gill C, Hickey E, Overbye KM, Barrett JF, Masurekar P. Antibacterial evaluations of thiazomycin- a potent thiazolyl peptide antibiotic from Amycolatopsis fastidiosa. J Antibiot (Tokyo). 2007;60:565.

    Article  CAS  PubMed  Google Scholar 

  19. Onishi HR, Pelak BA, Gerckens LS, Silver LL, Kahan FM, Chen MH, Patchett AA, Galloway SM, Hyland SA, Anderson MS, Raetz CR. Antibacterial agents that inhibit lipid A biosynthesis. C R Sci. 1996;274:980.

    CAS  Google Scholar 

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Correspondence to Sheo B. Singh.

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All authors were employed by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA where this work was conducted.

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Singh, S.B., Occi, J., Ondeyka, J. et al. Antibacterial and mechanism of action studies of boxazomycin A. J Antibiot 77, 679–684 (2024). https://doi.org/10.1038/s41429-024-00757-9

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