Advanced mutasynthesis studies on the natural α-pyrone antibiotic myxopyronin from Myxococcus fulvus

Chembiochem : a European Journal of Chemical Biology
Jan Henning SahnerRolf Müller

Abstract

Myxopyronin is a natural α-pyrone antibiotic from the soil bacterium Myxococcus fulvus Mx f50. Myxopyronin inhibits bacterial RNA polymerase (RNAP) by binding to a part of the enzyme not targeted by the clinically used rifamycins. This mode of action makes myxopyronins promising molecules for the development of novel broad-spectrum antibacterials. We describe the derivatization of myxopyronins by an advanced mutasynthesis approach as a first step towards this goal. Site-directed mutagenesis of the biosynthetic machinery was used to block myxopyronin biosynthesis at different stages. The resulting mutants were fed with diverse precursors that mimic the biosynthetic intermediates to restore production. Mutasynthon incorporation and production of novel myxopyronin derivatives were analyzed by HPLC-MS/MS. This work sets the stage for accessing numerous myxopyronin derivatives, thus significantly expanding the chemical space of f α-pyrone antibiotics.

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Citations

Dec 23, 2015·Natural Product Reports·Eric J N Helfrich, Jörn Piel
Oct 22, 2016·Cell Chemical Biology·Jakob Franke, Christian Hertweck
Dec 3, 2016·Natural Product Reports·J HerrmannR Müller
Oct 25, 2017·Medicinal Research Reviews·Gang Li, Hong-Xiang Lou
Jan 11, 2019·Chembiochem : a European Journal of Chemical Biology·Marius Grote, Frank Schulz
Jun 25, 2016·Beilstein Journal of Organic Chemistry·Till F Schäberle
May 19, 2021·Journal of Industrial Microbiology & Biotechnology·Dorothy A OkothRolf Müller
Aug 6, 2021·Chemical Science·Yuxiang ZhaoJingbo Chen

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