Structure-based design of peptides that triggerStreptococcus pneumoniaecell death

Toxin-antitoxin (TA) systems regulate key cellular functions in bacteria. Here, we report a unique structure of theStreptococcus pneumoniaeHigBA system and a novel antimicrobial agent that activates HigB toxin, which results in mRNA degradation as an antibacterial strategy. In this study, protein structure-based peptides were designed and successfully penetrated theS. pneumoniaecell membrane and exerted bactericidal activity. This result represents the time during which inhibitors triggeredS. pneumoniaecell death via the TA system. This discovery is a remarkable milestone in the treatment of antibiotic-resistantS. pneumoniae, and the mechanism of bactericidal activity is completely different from those of current antibiotics. Furthermore, we found that the HigBA complex shows a crossed-scissor interface with two intermolecular beta-sheets at both the N and C termini of the HigA antitoxin. Our biochemical and structural studies provided valuable information regarding the transcriptional regulation mechanisms associated with the structural variability of HigAs. Ourin vivostudy also revealed the potential catalytic residues of HigB and their functional relationships. An inhibition study with peptides additionally proved that peptide binding may allosterically inhibit HigB activity. Overall, our results provide insights into the molecular basis of HigBA TA systems inS. pneumoniae, which can be applied for the development of new antibacterial strategies. Databases Structural data are available in the PDB database under the accession number .

Automated summary

This study reveals a novel antimicrobial agent that activates HigB toxin to degrade mRNA as an antibacterial strategy against antibiotic-resistant Streptococcus pneumoniae, with a mechanism different from current antibiotics. Additionally, the structure of the HigBA complex and potential catalytic residues of HigB were identified, providing insights into the transcriptional regulation mechanisms and allosteric inhibition of HigB activity.