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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Saitoh, K; Konishi, M; Tomita, K, Boxazomycin A and B, new antibiotics containing benzoxazole nucleus, US 4,690,926, 1987.
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.
Suto MJ, Turner WR. Synthesis of Boxazomycin B and related analogs. Tetrahedron Lett. 1995;36:7213.
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.
Šlachtová V, Brulíková L. Benzoxazole derivatives as promising antitubercular agents. ChemistrySelect. 2018;3:4653.
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.
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.
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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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DOI: https://doi.org/10.1038/s41429-024-00757-9