Selective Mechanism Of A Ph-Responsive Peptide Beyond Ph-Response

Considering most studies on pH-responsive agents attribute the targeting effects to the pH-response, which cannot sufficiently explain the selection as both cariogenic and commensal bacteria live together in the same microenvironment, the research aim is to explore additional mechanisms to support the selective inhibition of a pH-responsive antimicrobial on Streptococcus mutans. The pH-response and selection of cariogenic bacteria were verified with transmission electron microscopy. Inhibition on F-ATPases was determined by a phosphate assay kit and molecular dynamics simulation. RNA-seq of S. mutans and Streptococcus gordonii was conducted to explore the effect differentiation on cariogenic bacteria and commensal bacteria. The acidic pH enhanced the disruption of S. mutans, while this acid-strengthened destructive effects were not so significant on commensal streptococci. The peptide directly inhibited the activity of F-ATPase by binding to its subunits. RNA-seq revealed that the peptide impacted stimulus response, substance transport, interspecies interaction, and basic biological processes of S. mutans, which contributed to the decreased environmental adaptability, viability and ecological competitiveness, while the peptide promote amino acid metabolism, cell wall modification, stimulus response and damage repair of S. gordonii, which contributed to its tolerance to the peptide and increase in ecological advantages. In addition to the targeting effect provided by the pH-response, the binding of LH12 to crucial membrane protein and different regulatory effects on cariogenic and commensal bacteria also perform important roles, suggesting its potential to regulate microecology and the importance of exploring undermining mechanisms.