Molecular basis of resistance to cytochrome bc1 inhibitors

Area of Science:

• Biochemistry
• Microbiology
• Molecular Biology

Background:

• Cytochrome bc1 (respiratory complex III) inhibitors are developed as antimicrobial agents.
• These inhibitors are effective against plant pathogenic fungi and human pathogens like Plasmodium falciparum and Pneumocystis jiroveci.
• Acquired resistance to these inhibitors is a significant challenge, often linked to mutations in the cytochrome b subunit.

Purpose of the Study:

• To review inhibitors of the mitochondrial respiratory chain enzyme cytochrome bc1.
• To discuss their mode of action and the mutations causing resistance.
• To analyze the impact of specific mutations on drug sensitivity, respiratory capacity, and cell fitness using Saccharomyces cerevisiae as a model.

Main Methods:

• Review of existing literature on cytochrome bc1 inhibitors and resistance mechanisms.
• Analysis of mutations within the cytochrome b gene.
• Utilizing Saccharomyces cerevisiae as a model organism to study mutation effects.

Main Results:

• Resistance to cytochrome bc1 inhibitors is frequently associated with mutations in the cytochrome b gene.
• Specific mutations have been identified that impact drug sensitivity, respiratory function, and cellular fitness.
• Yeast models provide valuable insights into the molecular basis of resistance.

Conclusions:

• Cytochrome bc1 inhibitors are broad-spectrum antimicrobials facing resistance issues.
• Understanding mutation-driven resistance is crucial for developing effective therapeutic strategies.
• Saccharomyces cerevisiae serves as a key model for studying resistance mechanisms and guiding future drug development.