Bi-functional Molecules

One of the intrinsic problems associated with chemotherapy of any infectious diseases is the development of drug resistance, as illustrated by the development of multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB. In TB, the development of drug resistance is reduced by using combination therapies that consist of three to four individual agents with different mechanisms of action. Resistance to each individual drug arises less readily because of the presence of other co-administered agents. A fundamentally different approach to combination therapy is to develop multifunctional molecules that, as the name suggests, possess multiple functional pharmacophores in the same molecule. A multi-functional molecule can therefore attack several drug targets simultaneously. Once optimized, it will prevent and treat drug resistant disease more effectively, provide synergy for better efficacy, and potentially overcome safety and tolerability issues associated with its parent compounds. The TB Alliance is developing multi-functional molecules that synergize the strengths of pharmacophores from the rifamycin, nitroimidazole, oxazolidinone, quinolone and other classes, while circumventing their resistance development liabilities and some safety and tolerability issues associated with the parent drugs. The rifamycin, nitroimidazole, oxazolidinone and quinolone classes of antibiotics have all shown particular promise as sources of new compounds that could shorten the duration of TB therapy and improve the treatment of drug resistance. Multi-functional antibiotics that utilize compounds from among these classes could prove significantly more effective against TB than any class alone, with the potential to both simplify and shorten TB drug therapy. Stage of Development: Lead optimization The project is currently exploring three bifunctional molecules: the rifamycin-nitroimidazoles, the quinolone-nitroimidazoles, and the nitroimidazole-oxazolidinones. In each case, a single new drug is created by covalently fusing together two existing pharmacophores based on the knowledge of their respective structure-activity relationships. Preliminary results have demonstrated dual functions of these molecules. In each class, promising bifunctional compounds have shown potent antibacterial activity. Optimization of one of these classes (nitroimidazole-oxazolidinones) has continued through 2009. Analogues have been prepared and tested in vitro to verify their multifunctional mode of action, and their improved resistance-development properties