Improving Antibiotic Efficacy Against Chronic Bacterial Infections

Staphylococcus aureus is the causative agent of numerous chronic and difficult to treat infections, including osteomyelitis (infection of bone), endocarditis (infection of the inner lining of the heart), infections of indwelling devices and cystic fibrosis lung infection. Even when resistance to an antibiotic is not observed, these infections respond poorly to treatment and often require surgical intervention. This is due to S. aureus ability to tolerate antibiotics, even at high concentrations. Tolerance is distinct from resistance as it is typically not genetically encoded, and the cells cannot grow in the presence of the antibiotic. Rather, a cell’s behavior, or phenotypic state, allows it to survive in high concentrations of antibiotics for extended periods. This can lead to relapse of infection once antibiotic treatment is ceased. 

Our goal is to determine how various factors in the infection environment can induce antibiotic tolerance in S. aureus and how this can impact the outcome of antibiotic treatment of infections. We use advanced methods, including mouse infection models and single cell analysis to determine the antibiotic tolerance of sub-populations in vitro and during infection. A thorough understanding of antibiotic susceptibility within the host is necessary to facilitate the improvement of treatment of chronic infection.

We are particularly interested in S. aureus in the cystic fibrosis lung and in chronic wound infections. These infections often respond poorly to antibiotics. We are keen to understand how interspecies bacterial interaction and host-pathogen interactions can determine antibiotic susceptibility and the outcome of infection. We recently demonstrated that P. aeruginosa exoproducts have a dramatic impact on S. aureus antibiotic susceptibility through three distinct pathways. 

We hope that our growing knowledge of antibiotic susceptibility determinants during infection will facilitate the improved use of existing antibiotics and the development of novel adjuvants to improve efficacy in vivo.