Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Microcin C (McC) is a peptide-nucleotide antibiotic that inhibits bacterial protein synthesis by targeting aspartyl-tRNA synthetase.
• McC producers possess self-resistance mechanisms to prevent self-toxicity from intracellular McC degradation products.
• The toxic metabolite of McC is an aspartamide-adenylate with a phosphoramide bond.

Purpose of the Study:

• To identify the resistance mechanisms employed by bacteria against microcin C (McC) and related compounds.
• To investigate the role of histidine-triad (HIT) hydrolases in conferring resistance to McC-like antibiotics.

Main Methods:

• Investigated the function of histidine-triad (HIT) hydrolases in the context of microcin C (McC) biosynthesis clusters and standalone genes.
• Assessed the ability of HIT hydrolases to hydrolyze the phosphoramide bond in toxic aspartamide-adenosine metabolites.

Main Results:

• Histidine-triad (HIT) hydrolases were found to confer resistance to microcin C (McC)-like compounds.
• HIT hydrolases inactivate the toxic aspartamide-adenosine metabolite by hydrolyzing its phosphoramide bond.
• This hydrolysis renders the toxic compound inactive, preventing inhibition of bacterial protein synthesis.

Conclusions:

• Universally conserved histidine-triad (HIT) hydrolases are key players in bacterial resistance to microcin C (McC).
• Understanding these resistance mechanisms is crucial for developing strategies against the growing antibiotic resistance crisis.
• HIT hydrolases offer a potential target for novel therapeutic approaches against bacterial infections.