Lüthy Lukas, Thies Leon Gabor Sacha, Beitl Konstantin Nikolaus, Hansen Moritz, McManus Joshua, Afzal Muhammad, Schrangl Lukas, Bloch Susanne, Subbiahdoss Guruprakash, Reimhult Erik, Schäffer Christina, Carreira Erick M
Department of Chemistry and Applied Biosciences, Laboratory of Organic Chemistry, ETH Zürich, 8093 Zürich, Switzerland.
Institute of Biochemistry, NanoGlycobiology Research Group, BOKU University, 1190 Vienna, Austria.
ACS Cent Sci. 2025 Mar 27;11(4):601-611. doi: 10.1021/acscentsci.4c02184. eCollection 2025 Apr 23.
Mutanofactins are a family of natural products produced by from the human oral microbiome. We report a unified approach to all mutanofactins by developing a total synthesis amenable to diversification. The key to success for the most complex members, mutanofactins 607 and 697, was an acyl ketene based strategy. Access to the family enabled comprehensive biological profiling, where we demonstrate that all mutanofactins are biofilm promoting in . Experiments were extended to other inhabitants of the oral microbiome for the first time: and , two early colonizers, were similarly affected with mutanofactins being biofilm promoting. Conversely, and showed little to no reaction to mutanofactins. Biophysical investigations based on quartz crystal microbalance with dissipation monitoring and atomic force microscopy reveal a previously unknown mucin-mutanofactin 697 interaction. Incubation of a mucin layer with mutanofactin 697 induces a morphology change within the mucin layer, which promotes bacterial adhesion and biofilm formation. This unique property of mutanofactin 697 might be key to early stages of biofilm formation in the human oral microbiome. Combined, an interdisciplinary approach consisting of total synthesis, microbiology and biophysical characterization provides insight into the roles of mutanofactins in the oral microbiome.
变聚糖因子是由人类口腔微生物群产生的一类天然产物。我们报告了一种通过开发适合多样化的全合成方法来合成所有变聚糖因子的统一方法。对于最复杂的成员变聚糖因子607和697，成功的关键是基于酰基乙烯酮的策略。能够合成该家族的所有成员使得能够进行全面的生物学分析，我们证明所有变聚糖因子在……中都能促进生物膜形成。实验首次扩展到口腔微生物群的其他成员：早期定植菌……和……，同样受到变聚糖因子促进生物膜形成的影响。相反，……和……对变聚糖因子几乎没有反应。基于具有耗散监测的石英晶体微天平以及原子力显微镜的生物物理研究揭示了一种以前未知的粘蛋白 - 变聚糖因子697相互作用。用变聚糖因子697孵育粘蛋白层会诱导粘蛋白层内的形态变化，从而促进细菌粘附和生物膜形成。变聚糖因子697的这种独特性质可能是人类口腔微生物群中生物膜形成早期阶段的关键。综合起来，由全合成、微生物学和生物物理表征组成的跨学科方法为深入了解变聚糖因子在口腔微生物群中的作用提供了思路。
