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Updated: Aug 18, 2025

Visualization of Bacterial Resistance using Fluorescent Antibiotic Probes
Published on: March 2, 2020
Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper
Yuya Nishida1,2, Sachiko Yanagisawa3, Rikuri Morita4
1Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Abstract:
Antimicrobial resistance (AMR) is a global health problem. Despite the enormous efforts made in the last decade, threats from some species, including drug-resistant Neisseria gonorrhoeae, continue to rise and would become untreatable. The development of antibiotics with a different mechanism of action is seriously required. Here, we identified an allosteric inhibitory site buried inside eukaryotic mitochondrial heme-copper oxidases (HCOs), the essential respiratory enzymes for life. The steric conformation around the binding pocket of HCOs is highly conserved among bacteria and eukaryotes, yet the latter has an extra helix. This structural difference in the conserved allostery enabled us to rationally identify bacterial HCO-specific inhibitors: an antibiotic compound against ceftriaxone-resistant Neisseria gonorrhoeae. Molecular dynamics combined with resonance Raman spectroscopy and stopped-flow spectroscopy revealed an allosteric obstruction in the substrate accessing channel as a mechanism of inhibition. Our approach opens fresh avenues in modulating protein functions and broadens our options to overcome AMR.
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