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- Title
Chemical genomics in Escherichia coli identifies an inhibitor of bacterial lipoprotein targeting.
- Authors
Pathania, Ranjana; Zlitni, Soumaya; Barker, Courtney; Das, Rahul; Gerritsma, David A.; Lebert, Julie; Awuah, Emilia; Melacini, Giuseppe; Capretta, Fred A.; Brown, Eric D.
- Abstract
One of the most significant hurdles to developing new chemical probes of biological systems and new drugs to treat disease is that of understanding the mechanism of action of small molecules discovered with cell-based small-molecule screening. Here we have assembled an ordered, high-expression clone set of all of the essential genes from Escherichia coli and used it to systematically screen for suppressors of growth inhibitory compounds. Using this chemical genomic approach, we demonstrate that the targets of well-known antibiotics can be identified as high copy suppressors of chemical lethality. This approach led to the discovery of MAC13243, a molecule that belongs to a new chemical class and that has a unique mechanism and promising activity against multidrug-resistant Pseudomonas aeruginosa. We show that MAC13243 inhibits the function of the LolA protein and represents a new chemical probe of lipoprotein targeting in bacteria with promise as an antibacterial lead with Gram-negative selectivity.
- Subjects
ANTIBACTERIAL agents; MOLECULAR genetics; BACTERIAL genetics; ESCHERICHIA coli; PSEUDOMONAS aeruginosa; BACTERIAL growth; MICROBIAL metabolites; LIPOPROTEIN drug carriers
- Publication
Nature Chemical Biology, 2009, Vol 5, Issue 11, p849
- ISSN
1552-4450
- Publication type
Article
- DOI
10.1038/nchembio.221