The treatment of tuberculosis has been complicated by the development of M. tuberculosis strains that are resistant to many, if not all, of the first-line drugs used to combat this infection. This has resulted in the increased use of second-line drugs in treatment regimens. As this reliance on second-line drugs grows, the development of M. tuberculosis strains that are resistant to these drugs will become increasingly problematic. Furthermore, many of these second-line drugs have unwanted complications, such as side- effects and means of delivery into the patient, that minimize their use. Since it has been more than 30 years since a new antibiotic to treat M. tuberculosis infections has been introduced into clinical use, it is of paramount importance that new methods for antituberculosis drug development be investigated. The tuberactinomycins are essential second-line drugs for the treatment of multidrug-resistant tuberculosis, but their wide-spread is limited due to unwanted side-effectsand the need for intramuscular injection during treatment of a patient. This proposal focuses on the discovery of new tuberactinomycin derivatives that have reduced side-effects, have more drug-like charateristics, and have activity against resistant strains. This will be accomplished by combining genetic and molecular engineering of the tuberactinomycin biosynthetic pathways, along with semi-synthetic chemistry.
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