S51 Family Peptidases Provide Resistance to Peptidyl-Nucleotide Antibiotic McC

Area of Science:

• Microbiology
• Biochemistry
• Molecular Biology

Background:

• Microcin C (McC)-like compounds are peptide-nucleotide antibiotics produced by bacteria.
• These antibiotics act as Trojan horses, entering susceptible cells and inhibiting essential protein synthesis by targeting aspartyl-tRNA synthetase.
• Bacteria producing these compounds possess resistance mechanisms to prevent self-intoxication.

Purpose of the Study:

• To identify novel mechanisms of bacterial resistance against microcin C-like compounds.
• To characterize the function of S51 family peptidases in the context of microcin C-like antibiotic resistance.
• To investigate the role of these peptidases in providing basal resistance across diverse bacterial species.

Main Methods:

• Identification and characterization of S51 family peptidases, termed MccG.
• Analysis of MccG's enzymatic activity on toxic isoaspartyl-nucleotide payloads.
• Genomic analysis to determine the distribution of MccG homologs in relation to microcin C-like compound biosynthesis gene clusters and as standalone genes.

Main Results:

• A new class of bacterial enzymes, MccG peptidases, was identified.
• MccG enzymes effectively cleave and inactivate the toxic isoaspartyl-nucleotide payload of microcin C-like antibiotics.
• MccG homologs are found both within microcin C-like compound biosynthesis gene clusters and as standalone genes in various bacteria, suggesting broad protective roles.

Conclusions:

• MccG peptidases represent a novel defense strategy employed by bacteria against microcin C-like antibiotics.
• These enzymes detoxify the antibiotic payload, preventing inhibition of aspartyl-tRNA synthetase.
• The widespread presence of MccG, particularly as standalone genes, indicates a significant contribution to basal resistance against peptide-nucleotide antibiotics in diverse bacterial populations.