US Patent:
20080027044, Jan 31, 2008
Inventors:
Kim Lewis - Newton MA, US
Gabriele Casadei - Cambridge MA, US
International Classification:
A61K 31/549
A61K 31/17
A61K 31/351
A61K 31/381
A61K 31/40
A61K 31/403
A61P 43/00
A61P 31/00
A61K 31/4184
A61K 31/435
A61K 31/498
A61K 31/4985
US Classification:
514223800, 514235200, 514256000, 514266400, 514267000, 514290000, 514312000, 514314000, 514394000, 514395000, 514411000, 514422000, 514443000, 514445000, 514448000, 514459000, 514585000, 514596000
Abstract:
Methods for identifying prodrug activity utilizing screens with microbial mutants, including null and conditional mutants, transiently gene-repressed microbes, and gene-overexpressing microbes, as well as pooled collections of these are provided. Effective prodrug antibiotics differentially kill or inhibit microbes overexpressing prodrug activating genes and allow non-expressing strains to grow and be readily identified. Methods for detecting prodrug antibiotic activity by detecting a lack of differential sensitivity of multidrug efflux mutant or deficient strains are also provided. Novel pharmaceutical compounds identified by the methods of the invention, pharmaceutical formulations, and methods for treating an infection comprising administering to a subject in need thereof an effective amount of a Compound of the Invention are also provided.