Sensitization of Bacterial Cells to Quinolone Antibiotic by Restoring High Energy Producing Metabolism

Technology

Quinolone treatment targets topoisomerases involved in DNA replication, however the metabolic state of bacteria can also affect quinolone sensitivity. In fact, bacteria are able to evade the killing effects of quinolones while in a metabolically lowered state due to oxygen and sugar shortage, as is common in high-density infections. These inventors are able to re-sensitize bacteria in this metabolically low state to quinolone treatment by providing fumarate as an alternative to oxygen as the terminal electron receptor in the electron transport chain.

Problem Addressed

Antibiotics are a critically important arsenal against bacteria and are indispensable in modern medicine. In recent years, antibiotic resistance has risen to dangerously high levels, leading to strains of bacteria that do not respond to antibiotics. Quinolones are a family of antibiotics commonly used to treat bacteria that have become resistant to first-line antibiotics. However, bacteria can also rapidly become resistant to quinolone therapy. Bacteria with metabolic exhaustion are often not killed by quinolone treatment, and this persistence has been identified as a state that promotes development of quinolone resistance. These inventors describe a strategy for sensitizing these metabolically exhausted bacteria to quinolone therapy.

Advantages

• Sensitization of bacteria to quinolone antibiotics
• Potential therapeutic technique to increase efficacy and decrease resistance to quinolone antibiotics

Publications

Arnaud Gutierrez, et al. Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics. Molecular Cell. 2017 Dec 07. doi: 10.1016/j.molcel.2017.11.012