In many chronic infections, including all biofilm related infections, the slow growth of bacteria is believed to account not only for resistance to antibiotics, but also for the high incidence of persistence and relapse. Considering that all currently prescribed antibiotics are significantly more effective against rapidly growing pathogens, the development of antibiotics highly effective against bacteria in the slow mode of growth is of utmost importance. By screening a chemical library for compounds bactericidal for slow-growing S. aureus, we have succeeded in identifying a very promising class of compounds, pyridinium thiol ethers (PTEs). Preliminary data indicate that PTEs are not only effective against fluid-phase S. aureus, but also against biofilms as well as against other bacteria in a slow mode of growth. In the proposed Phase I project, we will synthesize and screen a library of PTEs in order to identify compounds that will be bactericidal against slow and logarithmically growing S. aureus. Feasibility of the medical use of the most active derivatives will be analyzed. Finally, the basic principles underlying the molecular mechanism of action of PTE compounds will be investigated. The Phase I project will provide the basis for the Phase II project, which will involve chemical improvement of the lead compounds, investigation of their activity in various biofilm models, and in vivo toxicology studies. PTE compounds could provide a unique opportunity for eradication of infections associated with slow bacterial growth.
