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Depletion of antibiotic targets has widely varying effects on growth.

TitleDepletion of antibiotic targets has widely varying effects on growth.
Publication TypeJournal Article
Year of Publication2011
AuthorsWei J-R, Krishnamoorthy V, Murphy K, Kim J-H, Schnappinger D, Alber T, Sassetti CM, Rhee KY, Rubin EJ
JournalProc Natl Acad Sci U S A
Volume108
Issue10
Pagination4176-81
Date Published2011 Mar 08
ISSN1091-6490
KeywordsAnti-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.

DOI10.1073/pnas.1018301108
Alternate JournalProc Natl Acad Sci U S A
PubMed ID21368134
PubMed Central IDPMC3053961
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

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