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Pup protein with a fluorescent tag attached to it, that allows for screening of modulators of Dop activity, which may be subsequently developed as potential treatment options.
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Background Mycobacterium tuberculosis (Mtb)is one of the deadliest pathogens and the primary cause of Tuberculosis and Leprosy. Almost one-third of the world’s population is infected with Mtb and over a million deaths occur every year. The rod shaped bacterium infects phagocytic cells in the lungs of humans. Current therapies include a combination of antibiotics, which not only have limited efficacy due to the emergence of multi-drug resistant strains but also have severe side effects in patients. Therefore, there is an urgent requirement for the development of new and effective anti-mycobacterial drugs. To circumvent the problems associated with the increased appearance of antibiotic resistant Mtb strains and to also limit the side effects, the drug target should be in the pathogen and not in the patient. Full pathogenicity of requires its proteasome activityand involves several proteins including PafA (proteasome accessory factor A), Pup (prokaryotic ubiquitin-like protein) and Dop (deamidase of Pup). Interestingly, mice infected with Mtb mutated in pafA, dop and proteasome (prcBA) genes are unable to develop lethal Mtb infections and therefore these proteasome-related components could serve as potential drug targets. Description Dr. Darwin and colleagues have generated a modified Pup protein with a fluorescent tag attached to it, that allows for screening of modulators of Dop activity, which may be subsequently developed as potential treatment options for Mtb infections. To date, there is no known inhibitor for Dop amidase activity, thus representing a novel target for anti-tuberculosis drug development. The screening method can be used with bacterial cells lysates or isolated purified components and may be modified for high throughput assays. Application Since both Pup and Dop are essential for the virulence of Mtb, this invention will allow the identification of effective Pup and/or Dop inhibitors, which could be potentially developed asanti-tuberculosis and/or anti-leprosy therapeutics.