Title | Depletion of antibiotic targets has widely varying effects on growth. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Wei J-R, Krishnamoorthy V, Murphy K, Kim J-H, Schnappinger D, Alber T, Sassetti CM, Rhee KY, Rubin EJ |
Journal | Proc Natl Acad Sci U S A |
Volume | 108 |
Issue | 10 |
Pagination | 4176-81 |
Date Published | 2011 Mar 08 |
ISSN | 1091-6490 |
Keywords | Anti-Bacterial Agents, Bacteria, Bacterial Proteins, Hydrolysis, Molecular Sequence Data |
Abstract | It is often assumed that antibiotics act on the most vulnerable cellular targets, particularly those that require limited inhibition to block growth. To evaluate this assumption, we developed a genetic method that can inducibly deplete targeted proteins and that mimics their chemical inactivation. We applied this system to current antibiotic targets in mycobacteria. Although depleting some antibiotic targets significantly perturbs bacterial growth, surprisingly, we found that reducing the levels of other targets by more than 97% had little or no effect on growth. For one of these targets, dihydrofolate reductase, metabolic analysis suggested that depletion mimics the use of subinhibitory concentrations of the antibiotic trimethroprim. These observations indicate that some drug targets can exist at levels much higher than are needed to support growth. However, protein depletion can be used to identify promising drug targets that are particularly vulnerable to inhibition. |
DOI | 10.1073/pnas.1018301108 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 21368134 |
PubMed Central ID | PMC3053961 |
Grant List | / / Howard Hughes Medical Institute / United States P01 AI068135 / AI / NIAID NIH HHS / United States R01 AI071881 / AI / NIAID NIH HHS / United States R01AI071881 / AI / NIAID NIH HHS / United States P01AI68135 / AI / NIAID NIH HHS / United States |
Submitted by mam2155 on March 24, 2014 - 4:20pm