Chemical genomics in Escherichia coli identifies an inhibitor of bacterial lipoprotein targeting.
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.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Ranjana
R
Pathania
Soumaya
S
Zlitni
Courtney
C
Barker
Rahul
R
Das
David A
DA
Gerritsma
Julie
J
Lebert
Emilia
E
Awuah
Giuseppe
G
Melacini
Fred A
FA
Capretta
Eric D
ED
Brown
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002853:Chromatography, Liquid / Q000379:methods; D003523:Cycloserine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D029968:Escherichia coli Proteins / Q000187:drug effects / Q000378:metabolism; D005578:Fosfomycin / Q000031:analogs & derivatives / Q000494:pharmacology; D005798:Genes, Bacterial / Q000187:drug effects; D016680:Genome, Bacterial / Q000235:genetics*; D023281:Genomics / Q000379:methods; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D013058:Mass Spectrometry / Q000379:methods; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000187:drug effects; D033902:Periplasmic Binding Proteins / Q000187:drug effects / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics; D013420:Sulfamethoxazole / Q000494:pharmacology; D013489:Suppression, Genetic; D014295:Trimethoprim / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D008074:Lipoproteins; C116111:LolA protein, E coli; D018832:Molecular Chaperones; D033902:Periplasmic Binding Proteins; D005578:Fosfomycin; C024640:fosmidomycin; D004317:Doxorubicin; D003523:Cycloserine; D014295:Trimethoprim; D013420:Sulfamethoxazole