APPLICATION TITLE Elucidating physiology of dormant bacteria to combat antibiotic persistence PROJECT SUMMARY Most antibiotics are ineffective for killing dormant bacteria and it is estimated that 50% of antibiotic tolerance cases are due to phenotypic `persistence' rather than genetic resistance: bacteria can survive drug treatment simply because a few of them are metabolically dormant. For example, nutrient and oxygen depletion in the center of biofilms renders bacteria metabolically dormant and antibiotic tolerant. Once the antibiotic is withdrawn, recurrence gives bacteria the chance to evolve antibiotic resistance. Common examples of recurrent infections include urinary tract infections of pathogenic E. coli?the most common bacterial infection in women in developed countries?latent tuberculosis, and biofilm-forming bacteria, like the P. aeruginosa infections that often complicate wound healing and commonly affect cystic fibrosis patients. To develop new strategies to combat recurring infections and persistence, we need a better understanding of dormant bacteria. My laboratory aims to identify new antibiotic targets that are effective against dormant bacteria. By studying spontaneous death rates of dormant bacteria, we have already identified key vulnerabilities. We found that death rates of dormant bacteria critically depend on previous growth conditions. By correlating proteomics data with death rates, we have identified hundreds of genes that may contribute to survival and adaptation processes of dormant bacteria. We have validated many of our candidates using genetics, and discovered a crucial role of the bacterial outer membrane for the survival of dormant bacteria. We now need to uncover how the outer membrane mechanistically contributes to survival during dormancy and understand a complex interplay between the cell envelope, osmoregulation and energy metabolism that we have discovered. A better understanding of these processes will reveal the most promising antibiotic targets and effective combinations of existing drugs against dormant bacteria. My lab's interdisciplinary experience in quantitative biology and biophysics puts us in a unique position to answer these questions and to provide key insights into the physiology of dormant states.
Bacterial infections remain a leading cause of death, a problem that is aggravated by the limited effectiveness of antibiotics for killing slow-growing and dormant bacteria, such as recurrent E. coli urinary tract infections. We propose to elucidate how bacteria can survive prolonged dormant metabolic states and how this affects pathogenesis and treatment. Identifying molecular mechanisms of adaptability and survival in slow growing bacteria may uncover new targets for novel antibiotics.
