There is an urgent need for bactericidal antimicrobial agents effective against Gram positive infections. Although bacteriostatic antibiotics are useful in treating a large number of infections their activity can be limited in situations where it is imperative to eradicate an infection rather than simply stop bacterial growth. We have succeeded in identifying an extremely promising class of compounds, the lead of which, in combination with bacteriostatic concentrations of either erythromycin, chloramphenicol, clindamycin or tetracycline, is synergistically and rapidly bactericidal to S. aureus. Preliminary data indicate that this compound is also effective in S. pneumoniae. In this Phase I project the range of antibiotics potentiated by the lead compound and its bacterial spectrum of activity will be determined. QSAR analysis will be performed on purchased and chemically synthesized analogues of INF 401 with the view of chemically improving its activity and decreasing in vitro toxicity. Additionally the basic principles underlying the molecular mechanism of action of this intriguing compound will be investigated. The Phase I project will provide the basis for the Phase II project which will involve further chemical improvement of the lead compound and in vivo toxicology and efficacy studies.The developed potentiator, combined with existing bacteriostatic antibiotics, can provide a valuable therapeutic alternative when resistance to bactericidal antibiotics limits therapeutic options.
The envisioned commercial product is the combination of either a macrolide, lincosamide, tetracycline, chloramphenicol, or other bacteriostatic antibiotic, with a potentiator to give a combination that is bactericidal to a range of Gram positive pathogens. Such a combination would provide a valuable therapeutic alternative, especially when resistance to existing antibiotics limits therapeutic options.
