About AMR: Self-destruction in response to nutrient starvation is key to antibiotic activity

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A recently published study uncovers how an antibiotic that targets a metabolic pathway to starve bacteria of a nutrient can lead to cell death. The research sheds light on the downstream effects that can account for toxicity following the interaction of an antibiotic with its cellular target.

The consequence of nutrient starvation on bacteria is typically a reduction in cell growth. The exception, however, is starvation for thymine, which leads to lethality. This phenomenon is exploited by the antibiotic trimethoprim, which targets the folate synthesis pathway and blocks thymidine synthesis, inhibiting bacterial DNA synthesis. The exact mechanisms linking inhibition of a metabolic pathway to cell death, however, have remained incompletely understood.

In a recent study, published in the Proceedings of the National Academy of Sciences, Giroux and colleagues propose a model where treatment of Escherichia   coli with trimethoprim triggers production of potent oxidants that damage DNA and cause cellular lethality, providing a plausible mechanism to link nutrient starvation to cell death.

The authors demonstrate that upon treatment with trimethoprim, E. coli is starved of thymidine. This correlates with an induction of reactive oxygen species (ROS), thought to be the result of stalled DNA replication. When the authors added ROS detoxifying agents to trimethoprim-treated E. coli, the cells were protected, and when they inactivated cellular ROS detoxification systems, the cells were more sensitive, linking ROS production to cell toxicity.

ROS can lead to oxidative DNA damage in various forms, among which includes mutation of guanine to 8-oxoG. This mutation can be repaired by the mismatch repair pathway, which involves enzymes that remove the mutated base. Although these enzymes are aimed at repairing damage, the authors find that in their absence, E. coli is more tolerant to trimethoprim. The authors suggest that the repair enzymes are in fact harmful because they induce single-stranded DNA breaks that if left unrepaired, can lead to lethal double-stranded DNA breaks. This model is supported by the observation that inactivation of enzymes involved in double-stranded DNA break repair increases sensitivity to trimethoprim.

The authors further investigated cellular lethality under oxygen depleted conditions, since oxygen is required for production of ROS. They found that under these conditions, E. coli respired with nitrogen, generating reactive nitrogen products with similar DNA-damaging effects.

Interestingly, another study out this month in Nature Microbiology provides a slightly different sequence of events upon thymine starvation. In contrast to trimethoprim treatment, they find that stalling of DNA replication upon thymine starvation leads to single-stranded DNA breaks, an event that precedes ROS induction. ROS subsequently accumulates and further damages the single-stranded DNA breaks, promoting double-stranded DNA breaks and cell death.

Both studies reveal important roles for oxidative damage in triggering cell death in response to nutrient starvation – although the precise molecular events that trigger ROS accumulation, and whether these mechanisms are conserved in both situations, remain elusive. Continued research in this area will reveal important insight into stress-induced cell death – perhaps uncovering new ways to target antibiotic-resistant bacteria.

Sources:

  1. Giroux X, Su, WL, Bredech MF, Matic I. Maladaptive DNA repair is the ultimate contributor to the death of trimethoprim-treated cells under aerobic and anaerobic conditions. Proc. Natl Acad. Sci. 114(43),11512–11517 (2017)
  2. Hong Y, Li L, Luan G, Drlica K, Zhao X. Contribution of reactive oxygen species to thymineless death in Escherichia coli. Nat. Microbiol. doi:10.1038/s41564-017-0037-y (2017)

About the author

Julie Kaiser is a Ph.D. candidate in Microbiology at the University of Western Ontario in London, Canada. Her research interests range from the impact of microbial communities on human health, to the molecular basis of drug-resistant bacterial infections. Julie enjoys sharing her love for the microbial world through science communication and is the author of Microbiology for Dummies. Follow her on twitter at @jukais.

 

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