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Sulfonamide resistance: mechanisms and trends
1Division of Microbiology, Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Summary
Sulfonamide antibiotics target bacterial dihydropteroate synthase (DHPS). Resistance emerges through mutations and horizontal gene transfer, leading to drug-insensitive DHPS variants in pathogens.
Area of Science:
- Microbiology
- Drug Discovery
- Biochemistry
Background:
- Sulfonamides were early selective antibacterial agents targeting dihydropteroate synthase (DHPS).
- Widespread resistance has reduced their clinical use.
- Mammalian cells bypass the DHPS pathway by utilizing external folate.
Purpose of the Study:
- Investigate mechanisms of sulfonamide resistance in bacteria.
- Characterize drug-resistant dihydropteroate synthase variants.
- Understand the genetic basis of sulfonamide insensitivity.
Main Methods:
- Analysis of laboratory and clinical bacterial mutants.
- Gene sequencing of folP and resistance genes (sul1, sul2).
- Enzyme kinetics and substrate binding assays for DHPS variants.
Main Results:
- Laboratory mutants show a resistance-performance trade-off.
- Clinical resistance often involves horizontally transferred folP genes.
- Plasmid-borne sul1 and sul2 genes encode sulfonamide-insensitive DHPS variants.
- Resistant DHPS enzymes maintain p-aminobenzoic acid binding despite structural similarity to sulfonamides.
Conclusions:
- Horizontal gene transfer of alternative DHPS variants is a key mechanism for sulfonamide resistance.
- Resistant DHPS enzymes have evolved to evade sulfonamide inhibition while retaining substrate affinity.
- Understanding these resistance mechanisms is crucial for developing new antibacterial strategies.