Inhibitors of cytochrome c biogenesis pathways

Area of Science:

• Microbiology and Biochemistry
• Drug Discovery and Development
• Antimicrobial Research

Background:

• Bacterial electron transport chains (ETCs) differ from human mitochondrial ETCs, offering potential for selective antibacterial targeting.
• Bacterial cytochrome c (cyt c) biogenesis systems (I and II) are absent in mammals, making them promising novel antibiotic targets.
• Existing ETC inhibitors show promise, especially against mycobacteria.

Purpose of the Study:

• To screen FDA-approved compounds for inhibitors of bacterial cyt c biogenesis.
• To identify novel antibacterial agents targeting cyt c maturation pathways.
• To elucidate the mechanisms of action for identified inhibitors.

Main Methods:

• Screening of 1,760 FDA-approved compounds for inhibitors of *in vivo* bacterial cyt c biogenesis.
• Testing identified compounds for inhibition of purified cyt c synthases (*in vitro*).
• Assessing the effects of 8-hydroxyquinolines on bacterial growth and cyt c biogenesis.

Main Results:

• Seven compounds inhibited bacterial cyt c biogenesis systems I and/or II.
• Artemisinins (ARTs) directly inhibited *in vitro* cyt c biogenesis by disrupting heme in synthases.
• 8-hydroxyquinolines (8-HQs) inhibited *in vivo* cyt c biogenesis at low micromolar concentrations, likely via multiple mechanisms.
• 8-HQs did not directly inhibit *in vitro* cyt c synthases, suggesting indirect action.

Conclusions:

• Bacterial cyt c biogenesis is a viable antibacterial target distinct from human pathways.
• Artemisinins and 8-hydroxyquinolines represent two distinct classes of cyt c biogenesis inhibitors.
• Inhibition of cyt c biogenesis alone is insufficient for bacterial killing, supporting combination therapy approaches.
• These findings advance understanding of bacterial respiration and drug-heme interactions.