Despite the availability of effective chemotherapy and implementation of the Directly Observed Therapy, Short course strategy, tuberculosis (TB) remains a leading cause of adult deaths attributable to a single infectious disease. Standard multidrug therapy for TB requires a minimum of 6 months, and more than a year in drug resistant-TB patients. The long duration of chemotherapy has been associated with poor patient compliance and treatment failure. Since the antibiotics used to treat Mtb infection were selected for their ability to kill actively replicating bacilli, subpopulations of slow- and/or non-replicatng Mycobacterium tuberculosis (Mtb), thought to exist in the lungs of patients with active TB, remain alive and can show phenotypic tolerance after treatment completion, thus contributing to failure of TB treatment. Moreover, residual chronic lung damage, associated with increased risk for disease relapse and reinfection, has been reported in TB patients in spite of bacteriological cure. Here, we propose to improve the effectiveness of currently available anti-TB drugs through use of adjunctive immune modulation with a small molecule phosphodiesterase-4 inhibitor (PDE4i). For this study, we will use an established rabbit model of Mtb infection that closely mimics the pathologic features of TB disease in humans. We have demonstrated that Mtb isolates HN878 and CDC1551 elicit distinct clinical outcome following infection of rabbits. HN878 infection of rabbits results in chronic pulmonary TB with cavitary disease similar to what is seen in humans with active TB. Mtb CDC1551 infection of rabbits yields the only animal model that consistently results in full and spontaneous (i.e. not drug-mediated) clearance of bacteria and establishment of latent TB infection (LTBI) in the lungs. In previous studies using the PDE4i (CC11050) in Mtb infected rabbits, we showed that the drug is not generally immune suppressive, improves INH mediated Mtb killing, and reduces lung pathology. The drug has demonstrated safety in Phase I clinical trials in humans. However, these data are not sufficient to initiate human studies without the additional knowledge of how this adjunct treatment will act in a multi-drug TB regimen. The goal of this project is to test the ability of PDE4i (CC11050) to: a) accelerate Mtb clearance in a multi-drug regimen;b) reduce disease pathology to improve clinical outcome, and c) limit the risk of reactivation by enhancing the ability of multi-drug therapy to sterilize the infection. Results obtained from this preclinical study will facilitate th design and implementation of use of this novel PDE4i intervention in clinical trials, helping to achieve the ACTG's (AIDS Clinical Trial Group) agenda to develop shorter and more effective TB therapy.

Public Health Relevance

Current treatment of tuberculosis (TB) is hindered by several factors, including the long duration of chemotherapy to cure infection and residual lung damage. We propose to improve the effectiveness of anti-TB drugs through use of adjunctive immune modulation with a small molecule PDE4 inhibitor. Data obtained from the proposed preclinical studies are necessary for human clinical trials through the AIDS Clinical Trial Group (ACTG).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
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Srinivasan, Sudha
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Rutgers University
Public Health & Prev Medicine
Schools of Medicine
United States
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