Enabling Sciences Workgroup (ENS-WG) Q4-2015
The ENS-WG mission is to focus on discovery and validation of the molecular basis for resistance and correlation of resistance to clinical outcome.
- Discover relevant drug resistant mutations for potential use in molecular assays.
- Correlate genetic resistance mutations with phenotypic resistance and clinical outcomes.
- Optimize phenotypic assays.
- Review existing genotypic, phenotypic or animal data suggestive of background resistance to new drugs or cross resistance within the same class of drugs.
- Standardize test methods in partnership with commercialization partners to qualify MIC assays for new and old drugs.
- Collaborate with other Workgroups in the development of a RDST data-sharing platform.
- Collaborate with drug developers to clarify/interpret molecular drug resistance profiles.
- Understanding MOA and MOR to enable rapid DST development and evaluation of clinical isolates (both drug susceptible and drug resistant).
4Q, 2015 Progress:
- Lights On/Off assay platform:
- Completed the first round of testing. which currently includes 220 isolates. The assay examined 150 mutants and produced correct results for 114 (sensitivity of 80.6%). Aome additional refinement should correct false-positive readings for the remaining mutants.
- The team presented test results at 2015 Union Conference in Cape Town, South Africa.
- Posey (CDC) completed the examination of all possible pncA polymorphisms and their functional association with pyrazinamide. Results indicated that the majority of polymorphic codons conferred drug resistance to pyrazinamide.
- Posey led a multisite evaluation of the MGIT pyrazidamide assay. 10 APHL labs completed assessing the accuracy and reproducibility of the modified inoculation procedure to reduce false-positive rates. These labs are in the process of analyzing their data. Current results suggest that diluted inoculation decreases the probability of false resistance.
- Trek Plate project:
- An MTA between D. Cirillo’s lab and ThermoFisher has been executed.
- Cirillo’s lab has completed the initial evaluation of bedaquiline-only dried plates run in triplicate. There is a paradoxical effect that shows growth at higher concentrations and no growth at the lowest concentration for ofloxacin and ethambutol. This result was consistent across all plates, and is consistent with reports from the field. Although the preliminary data looks very good for bedaquiline, additional analysis and completion of all strains will occur in Q1, 2016 as scheduled.
- The ENS-WG is discussing additional sites with DAIDS to conduct multi-site clinical evaluations. Currently, the project awaits funder feedback on these other sites, which will improve the diversity of strains. Several countries from Southeast Asian have been recruited (Burma, Thailand, and Vietnam) and plan to participate.
- Interlock calls began between CPTR, Oxford, ThermoFisher and the Cirillo lab to ensure timely communications to proactively identify and address logistical issues and potential schedule delays.
- The MTA between ThermoFisher and Otsuka is complete. ThermoFisher initiated plate manufacturing, and expect to ship for testing in January.
- Oxford has shared their project gantt chart which will be used to monitor progress and keep within the timelines.