Each month, the OVPR highlights the past month’s sponsored research funding awarded to Tufts’ investigators, including both a list of funded awards and one or more featured project abstracts.
You can download the list of November’s awardees by clicking the button below. In November, Tufts researchers received 34 awards for extramural funding from federal, foundation, and corporate sponsors.
To submit a recent award to be highlighted, please use the "nominate a project" button below.
This month we are highlighting Dr. Bree Aldridge, for her Bill and Melinda Gates Foundation funded project, ‘Rapid drug response profiling of Mycobacterium tuberculosis with high content imaging.’ Please see the abstracts for these projects below.
PI: Bree Aldridge
Funder: Bill and Melinda Gates Foundation
Title: Rapid drug response profiling of Mycobacterium tuberculosis with high content imaging
Abstract: Tuberculosis (TB) treatment requires the simultaneous administration of multiple drugs to limit the emergence of drug resistance and ensure killing of a heterogeneous bacterial population. Drug tolerance in the host environment is thought to be a primary driver of the need for lengthy, multi-drug TB therapy. However, we have a poor understanding of how Mycobacterium tuberculosis (Mtb) adaptation to the host environment enables tolerance to drug-stressors. Key to the rational design of improved therapeutic regimens are methods to rapidly profile drug action in the context of the bacterial microenvironment and other elements of the treatment regimen including additional antibiotics and the timing/dosing of treatment. In preliminary work, we have adapted a tool called bacterial cytological profiling (BCP) to establish phase diagrams that map stressors and cellular response using morphological features. These shape and organization attributes are quantified by automatically analyzing images of bacteria stained with membrane and DNA markers. BCP works by quantifying cytological features before and after drug treatment to develop profiles that can be used to classify the stress response. In other bacteria, BCP has led to the rapid discovery of drug mechanisms of action and characterization of drug susceptibility (1-3). Though broadly translatable to many bacterial species, BCP has yet to be implemented in Mtb because of the significant variation among single cells and technical challenges
with quantitative imaging and throughput. We have made significant progress overcoming these experimental and analytic challenges to develop phenotypic profiles to classify Mtb treated with antibiotics
To design improved drug regimens and novel therapeutics, we need methods to rapidly characterize bacterial state in response to complex stressors introduced by the host and treatment. This would enable us to efficiently identify target pathways of existing and emergent drug classes in the context of Mtb adaption to host-relevant microenvironments. To address this problem, we propose here to further develop a platform for the rapid evaluation of Mtb stress response using BCP. We aim to construct a more complete phase diagram of stress responses to single-drugs in defined host-like stress conditions (Aim 1), determine mechanisms of drug interactions by profiling Mtb following multi-drug treatment (Aim 2), and measure how different clinical Mtb isolates respond to combinations of drug and environmental stressors (Aim 3). With these three aims, we will be able to explore a highly dimensional phase space of BCP; these dimensions will include Mtb strain, growth environment, treatment time, drug combination, and drug dose. Our goal is to explore this large space in an efficient manner by focusing on the most information-rich experimental permutations. To do so requires iterative experimental design and analysis.