Incomplete base excision repair contributes to cell death from antibiotics and other stresses

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Lethal bacterial stresses, including antibiotics and thymineless death, elevate reactive oxygen species (ROS) production.
• ROS, generated via Fenton chemistry, oxidize the intracellular nucleotide pool.
• Incorporation of oxidized nucleotides into DNA leads to genome damage.

Purpose of the Study:

• To review evidence linking incomplete base excision repair (BER) to cell death under stress.
• To explore the causal role of BER in mediating lethality from oxidative stress.
• To discuss the therapeutic potential of targeting this pathway for novel antibiotic development.

Main Methods:

• Literature review of studies on bacterial stress responses.
• Analysis of the role of reactive oxygen species and nucleotide oxidation.
• Examination of the base excision repair pathway's involvement in cell death.

Main Results:

• Oxidized nucleotides are incorporated into bacterial genomes during stress.
• Failed attempts by the base excision repair (BER) system to repair these lesions are a key factor in bacterial lethality.
• This incomplete BER-mediated cell death is a common mechanism across various lethal stresses.

Conclusions:

• Incomplete base excision repair (BER) is a significant contributor to bacterial cell death under stress.
• Understanding this pathway provides a novel target for antimicrobial drug discovery.
• Targeting BER could lead to the development of new antibiotics to combat bacterial infections.