The continued global prevalence of tuberculosis and the increased emphasis on the development of new anti-tuberculosis drugs has resulted in greater clinical trials activities to assess drug efficacies and treatmentstrategies. However, the amount of time required to perform clinical trials for new anti-tuberculosis drugs andtreatments needs to be shortened to allow for acceleration of the drug development pipeline. Current researchefforts must be applied to develop biomarkers or biosignatures that predict treatment outcomes much earlierthan the conversion of sputum to culture negative after two-months of treatment. The development ofbiomarkers is also needed to facilitate clinical trials with patients that do not present with the pulmonary form oftuberculosis. Moreover, the continued emergence of drug resistant (including MDR and XDR) strains ofMycobacterium tuberculosis and associated treatment failures underscores the need for biomarker orbiosignatures that serve could serve as a prognostic of treatment response. A comparison by liquidchromatography-mass spectrometry (LC/MS) of urine collected from tuberculosis patients at four time pointsduring drug treatment (day-0, two-weeks, one- or two-months, and six-months) has allowed us to develop asignature of over 50 small molecules present in the urine at the time of TB diagnosis, but that significantlydropped in abundance by two weeks of treatment and remained at low levels or disappeared at one or twomonths of treatment. Similar metabolomic studies with plasma collected from tuberculosis patients in SouthAfrica at day-0 and one-month also demonstrated differences in the metabolic profiles at these two time points.These studies provide proof-of-principal that metabolic fluxes in urine or plasma/sera during the treatment oftuberculosis produce a biosignature of effective treatment or cure. We now propose to expand these studies toaddress Objective 5 (Development of Diagnostics) of the FDA Office of Critical Path Programs' RFA SF424RR. More specifically, develop 'diagnostic biomarkers that will be reliable surrogates for determination ofrelapse free cures and prediction of relapse in TB clinical trials'. We will synergize our expertise in analyticalmass spectrometry and biomarker discovery with the existing resources of clinical trials that target or involvethe treatment of tuberculosis patients. These partnerships will provide large data sets of metabolic signaturesfor validation of existing biomarkers/biosignatures and development of new biosignatures that are not biasedby geographical location or underlying conditions such as HIV infection or treatment.
The proposed research will provide data to identify products in the urine and serum of tuberculosis patients that change in abundance with treatment of the disease. This information will allow the development of assays and biological signatures that can be used to predict the outcome of drug treatment for individual tuberculosis patients. The ability to integrate these measures into clinical trials holds great promise to reduce the amount of time and costs required to evaluate the efficacy of new anti-tuberculosis drugs and treatments.
