A novel approach to combating antibiotic resistance: Inhibition of mutation as a therapeutic strategy

The continual emergence of antibiotic-resistant pathogens represents a major threat to human health. In fact, bacteria now exist that are essentially untreatable by all of our conventional drugs. This alarming trend is due to the fact that bacteria are constantly evolving drug resistance through the generation of diversity (by mutation) and through natural selection of strains with increased drug resistance. Mutation has long been thought to be a passive process, however observations over the past several decades have fueled a new perspective on the process of mutagenesis: that under some conditions it is an active, regulated process that requires specific enzymes to function efficiently. Some of the conditions that have been shown to induce mutagenesis include DNA damage, extended periods of starvation, and the stress associated with antibiotic treatment.; Our work seeks to investigate the possibility of intervening in the active mutation process as a means to prevent or significantly delay the development of antibiotic resistance. We investigate the mechanism of ciprofloxacin-induced mutagenesis in the bacterium Escherichia coli and define which proteins are required for induced mutation in vitro and in a mouse infection model. In addition, we define the cellular response to ciprofloxacin and the induced mutation pathways of the important human pathogens, Pseudomonas aeruginosa and Staphylococcus aureus. We then characterize a mutant of Pseudomonas aeruginosa that has evolved resistance to ciprofloxacin by a non-canonical mechanism, by slowing its growth rate. Finally, we develop a high-throughput assay to identify potential inhibitors of the induced mutation process. In total, we demonstrate that the inhibition of mutation is a viable therapeutic strategy; this may have tremendous public health benefits and would represent a completely new frontier in medicine.