wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs

J Med Chem. 2014 Mar 27;57(6):2498-510. doi: 10.1021/jm401785n. Epub 2014 Feb 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology*
  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / pharmacology
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacology*
  • Chlamydia / drug effects
  • Herbicides / chemical synthesis
  • Herbicides / pharmacology
  • Humans
  • Hydrogen-Ion Concentration
  • Microbial Sensitivity Tests
  • Molecular Weight
  • Peas
  • Plants
  • Porphobilinogen Synthase / antagonists & inhibitors*
  • Porphyrias / drug therapy
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / enzymology
  • Rickettsia / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship
  • Wolbachia / drug effects

Substances

  • Anti-Bacterial Agents
  • Antiprotozoal Agents
  • Benzimidazoles
  • Herbicides
  • Porphobilinogen Synthase