Sensitizing Antibiotic-Tolerant Bacteria to Topoisomerase Inhibitors to Reduce Infection Relapse and Resistance Development

Antibiotic treatment failure poses a burden on global public health systems. Bacteria can acquire mutations and extrachromosomal genes that allow them to be resistant to our existing drugs. In addition to developing resistance, some bacteria in genetically clonal populations, coined persisters, can reversibly reprogram their phenotypic responses, enabling them to endure antimicrobial therapy and resume growth once treatment terminates. While the persister phenotype is not heritable, persistence is thought to contribute to infection relapse and accelerate resistance development, which motivates us to elucidate defenses that persisters depend on to survive antibiotic treatment. In this presentation, we focus on antibiotic persistence to DNA-damaging topoisomerase inhibitors. We show that persisters originating from slow-/non-growing cultures suffer DNA damage during topoisomerase inhibitor treatment, and they need to repair their DNA during the post-antibiotic treatment recovery period. We also found that persisters depend on multidrug efflux pumps to survive treatment with certain compounds that inhibit topoisomerases. Finally, we explore metabolic, biochemical, and microbial competition-basedapproaches to sensitize bacterial persisters to our existing and emerging topoisomerase inhibitors.

Learning Objectives:

1. Describe how bacterial phenotypic heterogeneity and antibiotic persistence contribute to antibiotic treatment failure.

2. Discuss the defenses that bacterial persisters depend on the survive treatment with topoisomerase inhibitors.

3. Describe methods of sensitizing bacterial persisters to existing and emerging topoisomerase inhibitors.