Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, TX, USA.
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA.
Nat Microbiol. 2024 Feb;9(2):502-513. doi: 10.1038/s41564-023-01583-9. Epub 2024 Jan 16.
Probiotic supplements are suggested to promote human health by preventing pathogen colonization. However, the mechanistic bases for their efficacy in vivo are largely uncharacterized. Here using metabolomics and bacterial genetics, we show that the human oral probiotic Streptococcus salivarius K12 (SAL) produces salivabactin, an antibiotic that effectively inhibits pathogenic Streptococcus pyogenes (GAS) in vitro and in mice. However, prophylactic dosing with SAL enhanced GAS colonization in mice and ex vivo in human saliva. We showed that, on co-colonization, GAS responds to a SAL intercellular peptide signal that controls SAL salivabactin production. GAS produces a secreted protease, SpeB, that targets SAL-derived salivaricins and enhances GAS survival. Using this knowledge, we re-engineered probiotic SAL to prevent signal eavesdropping by GAS and potentiate SAL antimicrobials. This engineered probiotic demonstrated superior efficacy in preventing GAS colonization in vivo. Our findings show that knowledge of interspecies interactions can identify antibiotic- and probiotic-based strategies to combat infection.
益生菌补充剂被认为可以通过预防病原体定植来促进人类健康。然而,其在体内的功效的机制基础在很大程度上还没有被描述。在这里,我们使用代谢组学和细菌遗传学的方法,表明人类口腔益生菌唾液链球菌 K12(SAL)产生唾液菌素,这是一种抗生素,可有效抑制体外和小鼠体内的致病性酿脓链球菌(GAS)。然而,预防性给予 SAL 会增强小鼠和人体唾液中的 GAS 定植。我们表明,在共同定植时,GAS 对 SAL 细胞间肽信号做出反应,从而控制 SAL 唾液菌素的产生。GAS 产生一种分泌蛋白酶 SpeB,该酶靶向 SAL 衍生的唾液酸,并增强 GAS 的存活。利用这一知识,我们重新设计了益生菌 SAL,以防止 GAS 对信号的窃听并增强 SAL 的抗菌作用。这种经过工程改造的益生菌在预防 GAS 定植方面表现出更好的功效。我们的研究结果表明,对种间相互作用的了解可以确定基于抗生素和益生菌的策略来对抗感染。