The Peptide Antibiotic Corramycin Adopts a β-Hairpin-like Structure and Is Inactivated by the Kinase ComG

Area of Science:

• Microbiology
• Biochemistry
• Structural Biology

Background:

• Antibiotic resistance in Gram-negative bacteria is a major public health threat.
• Understanding novel resistance mechanisms is key to combating resistance.
• Corramycin is a new peptide antibiotic effective against Gram-negative pathogens.

Purpose of the Study:

• To identify and characterize the mechanism of corramycin resistance.
• To elucidate the structure and function of the ComG kinase.
• To assess the potential of corramycin as a future antibiotic.

Main Methods:

• Biochemical assays to study kinase activity and substrate specificity.
• Crystallography to determine the structure of ComG in complex with corramycin.
• Bioinformatic analysis of ComG homologues.

Main Results:

• The kinase ComG inactivates corramycin via phosphorylation, conferring host resistance.
• ComG's closest structural relatives are aminoglycoside phosphotransferases, but ComG lacks activity against them.
• Structural analysis revealed corramycin's beta-hairpin structure and the basis for ComG's peptide substrate specificity.

Conclusions:

• ComG represents a novel mechanism of antibiotic resistance.
• Corramycin's unique resistance profile and ComG's specific activity suggest low cross-resistance potential.
• Corramycin is a promising candidate for further antibiotic development.