Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper...

Area of Science:

• Biochemistry
• Microbiology
• Drug Discovery

Background:

• Antimicrobial resistance (AMR) poses a significant global health threat, with increasing cases of untreatable infections.
• Drug-resistant Neisseria gonorrhoeae is a critical concern requiring novel therapeutic approaches.

Purpose of the Study:

• To identify novel antibiotic targets and develop inhibitors against drug-resistant bacterial pathogens.
• To explore the potential of targeting heme-copper oxidases (HCOs) for antimicrobial drug development.

Main Methods:

• Identified a conserved allosteric inhibitory site within eukaryotic mitochondrial heme-copper oxidases.
• Utilized molecular dynamics, resonance Raman spectroscopy, and stopped-flow spectroscopy to investigate inhibition mechanisms.
• Designed and identified a specific inhibitor targeting bacterial HCOs.

Main Results:

• Discovered a conserved allosteric site in HCOs, differentiating bacterial and eukaryotic forms.
• Developed a novel antibiotic compound effective against ceftriaxone-resistant Neisseria gonorrhoeae.
• Elucidated the inhibition mechanism as allosteric obstruction of the substrate access channel.

Conclusions:

• The study presents a rational drug design approach targeting a conserved bacterial enzyme.
• This strategy provides a promising new avenue for developing antibiotics to overcome AMR.
• The findings open new possibilities for modulating protein functions to combat resistant infections.