Synergistic action of specialized metabolites from divergent biosynthesis in the human oral microbiome

• 成果类型: Article
• 署名作者: Yao, McKenna Loop; Zill, Nicholas A.; Barber, Colin Charles; Du, Yongle; Lin, Peijun; Zhai, Rui; Yoon, Eunice; Al Marzooqi, Dunya; Zhang, Wenjun
• 署名单位: University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11683
• DOI: 10.1073/pnas.2504492122
• 发表日期: 2025-08-26
• 关键词: streptococcus-mutans; polyketide; adsorption; repository; tolerance; virulence

摘要

Despite extensive efforts, our understanding of the virulence factors contributing to oral biofilm formation-a hallmark of dental caries-remains incomplete. We present evidence that the specialized metabolism of the oral microbiome is a critical yet under-explored factor in oral biofilm formation. Through microbiome analysis, we identified a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) encoding biosynthetic gene cluster that correlates with dental caries and is widely represented in oral pathogens, including Streptococcus mutans. This gene cluster produces two major mutanoclumpin metabolites, MC-584 and MC-586, which feature molecular scaffolds differing in a C-C macrocyclic linkage. Both metabolites synergistically promote robust biofilm formation of S. mutans through a rare dual-metabolite mode of action. Further, each metabolite binds uniquely to the S. mutans cell surface, resulting in distinct multi-cellular morphologies. The biosynthesis of mutanoclumpins employs a unique chemical logic that produces two major products, rare within PKS-NRPS assembly lines. This study underscores the importance of characterizing genes implicated in human diseases through microbiome analysis and lays the foundation for exploring strategies to inhibit streptococci-induced dental caries.