Nguyen Dieu Linh, Saha Subhasree, Thacharodi Aswin, Singh Bharat Bhushan, Mitra Sonali, Do Hackwon, Kumaraswami Muthiah
Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA.
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.
J Bacteriol. 2025 Jun 24;207(6):e0005925. doi: 10.1128/jb.00059-25. Epub 2025 Jun 2.
K12 (SAL) is an oral probiotic used to treat or prevent oral infections caused by human pathogens. SAL produces at least three antimicrobials to exert its antimicrobial activity, namely, salivaricin A and salivaricin B, and the newly identified salivabactin. Salivabactin production is catalyzed by a polyketide/non-ribosomal peptide synthase hybrid biosynthetic gene cluster (BGC), termed as . The expression and salivabactin production are transient during SAL growth and , which may negatively impact SAL probiotic efficacy. To understand the molecular basis for transient expression, we assessed the impact of environmental pH on expression. We found that environmental acidification is a critical factor in promoting salivabactin antimicrobial activity and production by inducing expression. We further showed that acidic pH directly influences the quorum-sensing system that controls expression. During environmental acidification, SAL cytosol is acidified, which is sensed by a pH-sensitive histidine switch in the cytosolic transcription regulator, NrpR. The protonation of histidine during cytosolic acidification promotes high-affinity interactions between NrpR and its cognate intercellular signaling peptide, NIP, which leads to upregulation of expression. Collectively, our results indicate that SAL uses a sophisticated regulatory mechanism to orchestrate salivabactin production in an environment that is conducive to its antimicrobial activity.
Probiotic bacteria are important tools in combating bacterial infections. Probiotics exert their antimicrobial activity via several mechanisms, including antimicrobial production. However, discrepancies exist between the and efficacies of probiotics in inhibiting pathogen growth. Understanding the host and environmental factors that influence antimicrobial production and activity is critical for improving probiotic efficacy. In this study, we showed that the antimicrobial salivabactin produced by human oral probiotic K12 is active at acidic pH. We further elucidated the molecular mechanism by which coordinates salivabactin production in concert with environmental acidification, thereby maximizing salivabactin antimicrobial activity.
K12（唾液乳杆菌）是一种口服益生菌，用于治疗或预防由人类病原体引起的口腔感染。唾液乳杆菌产生至少三种抗菌物质来发挥其抗菌活性，即唾液乳杆菌素A和唾液乳杆菌素B，以及新发现的唾液杆菌素。唾液杆菌素的产生由一个聚酮/非核糖体肽合成酶杂交生物合成基因簇（BGC）催化，称为 。在唾液乳杆菌生长 和 期间， 的表达和唾液杆菌素的产生是短暂的，这可能会对唾液乳杆菌的益生菌功效产生负面影响。为了了解 短暂表达的分子基础，我们评估了环境pH对 表达的影响。我们发现环境酸化是通过诱导 表达来促进唾液杆菌素抗菌活性和产生的关键因素。我们进一步表明，酸性pH直接影响控制 表达的群体感应系统。在环境酸化期间，唾液乳杆菌的细胞质被酸化，这由细胞质转录调节因子NrpR中的pH敏感组氨酸开关感知。细胞质酸化期间组氨酸的质子化促进了NrpR与其同源细胞间信号肽NIP之间的高亲和力相互作用，从而导致 表达上调。总的来说，我们的结果表明，唾液乳杆菌利用一种复杂的调节机制，在有利于其抗菌活性的环境中协调唾液杆菌素的产生。
益生菌是对抗细菌感染的重要工具。益生菌通过多种机制发挥其抗菌活性，包括产生抗菌物质。然而，益生菌在抑制病原体生长方面的 和 功效之间存在差异。了解影响抗菌物质产生和活性的宿主和环境因素对于提高益生菌功效至关重要。在这项研究中，我们表明人类口腔益生菌K12产生的抗菌物质唾液杆菌素在酸性pH下具有活性。我们进一步阐明了 与环境酸化协同协调唾液杆菌素产生的分子机制，从而最大限度地提高唾液杆菌素的抗菌活性。
