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Schlagwörter:
Animals Anti-Bacterial Agents/*chemical synthesis/*pharmacology Antiprotozoal Agents/chemical synthesis/pharmacology Benzimidazoles/*chemical synthesis/*pharmacology Chlamydia/drug effects Herbicides/chemical synthesis/pharmacology Humans Hydrogen-Ion Concentration Microbial Sensitivity Tests Molecular Weight Peas Plants Porphobilinogen Synthase/*antagonists & inhibitors Porphyrias/drug therapy Pseudomonas aeruginosa/drug effects/enzymology Rickettsia/drug effects Stereoisomerism Structure-Activity Relationship Wolbachia/drug effects
Zusammenfassung:
The heme biosynthesis enzyme porphobilinogen synthase (PBGS) is a potential drug target in several human pathogens. wALADin1 benzimidazoles have emerged as species-selective PBGS inhibitors against Wolbachia endobacteria of filarial worms. In the present study, we have systematically tested wALADins against PBGS orthologs from bacteria, protozoa, metazoa, and plants to elucidate the inhibitory spectrum. However, the effect of wALADin1 on different PBGS orthologs was not limited to inhibition: several orthologs were stimulated by wALADin1; others remained unaffected. We demonstrate that wALADins allosterically modulate the PBGS homooligomeric equilibrium with inhibition mediated by favoring low-activity oligomers, while 5-aminolevulinic acid, Mg(2+), or K(+) stabilized high-activity oligomers. Pseudomonas aeruginosa PBGS could be inhibited or stimulated by wALADin1 depending on these factors and pH. We have defined the wALADin chemotypes responsible for either inhibition or stimulation, facilitating the design of tailored PBGS modulators for potential application as antimicrobial agents, herbicides, or drugs for porphyric disorders.
