Jeffers, Victoria and Kamau, Edwin T. and Srinivasan, Ananth R. and Harper, Jonathan and Sankaran, Preethi and Post, Sarah E. and Varberg, Joseph M. and Sullivan, William J. and Boyle, Jon P. and Phillips, Margaret
(2017)
TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite Toxoplasma gondii.
mSphere, 2 (1).
ISSN 2379-5042
Abstract
New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite’s replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the “reader” module of acetylated lysines. In independent studies, we sought to determine the targets of these two compounds using forward genetics, generating resistant mutants and identifying the determinants of resistance with comparative genome sequencing. Despite the dissimilarity of the two compounds, we recovered resistant mutants with nonsynonymous mutations in the same domain of the same gene, TGGT1_254250, which we found encodes a protein that localizes to the parasite mitochondrion (designated TgPRELID after the name of said domain). We found that mutants selected with one compound were cross resistant to the other compound, suggesting a common mechanism of resistance. To further support our hypothesis that TgPRELID mutations facilitate resistance to both I-BET151 and F3215-0002, CRISPR (clustered regularly interspaced short palindromic repeat)/CAS9-mediated mutation of TgPRELID directly led to increased F3215-0002 resistance. Finally, all resistance mutations clustered in the same subdomain of TgPRELID. These findings suggest that TgPRELID may encode a multidrug resistance factor or that I-BET151 and F3215-0002 have the same target(s) despite their distinct chemical structures.
IMPORTANCE We report the discovery of TgPRELID, a previously uncharacterized mitochondrial protein linked to multidrug resistance in the parasite Toxoplasma gondii. Drug resistance remains a major problem in the battle against parasitic infection, and understanding how TgPRELID mutations augment resistance to multiple, distinct compounds will reveal needed insights into the development of new therapies for toxoplasmosis and other related parasitic diseases.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
Article
|
| Status: |
Published |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Jeffers, Victoria | | | | | Kamau, Edwin T. | | | | | Srinivasan, Ananth R. | | | | | Harper, Jonathan | | | | | Sankaran, Preethi | | | | | Post, Sarah E. | | | | | Varberg, Joseph M. | | | | | Sullivan, William J. | | | | | Boyle, Jon P. | boylej@pitt.edu | | | | Phillips, Margaret | | | |
|
| Date: |
17 February 2017 |
| Date Type: |
Publication |
| Journal or Publication Title: |
mSphere |
| Volume: |
2 |
| Number: |
1 |
| Publisher: |
American Society for Microbiology |
| DOI or Unique Handle: |
10.1128/msphere.00229-16 |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Biological Sciences |
| Refereed: |
Yes |
| ISSN: |
2379-5042 |
| Official URL: |
http://dx.doi.org/10.1128/mSphere.00229-16 |
| Article Type: |
Research Article |
| Date Deposited: |
08 Jun 2020 13:02 |
| Last Modified: |
08 Jun 2020 13:02 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39146 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Altmetric.com
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}