Mutation-Induced Conformational Remodeling of Dihydropteroate Synthase Governs Sulfonamide Resistance in Streptococcus pneumoniae.

Mutations in Streptococcus pneumoniae DHPS alter the catalytic cavity and substrate tunnel, reducing sulfamethoxazole binding and conferring resistance.

• Why it matters: Understanding the molecular basis of DHPS mutation-mediated resistance is crucial for addressing environmental antimicrobial resistance and improving antibiotic design.
• What they did: Six clinically relevant DHPS mutants were constructed from resistant isolates, and their structural effects on ligand recognition and binding modes were analyzed through structure-activity relationship studies.
• The result: Mutations primarily weaken SA binding by expanding loops and impairing loop closure, with fused-ring sulfonamides showing the strongest tolerance, revealing mechanisms that preserve substrate recognition while conferring resistance.