Abstract:
:The general secretion (Sec) pathway is a conserved essential pathway in bacteria and is the primary route of protein export across the cytoplasmic membrane. During protein export, the signal peptidase LepB catalyzes the cleavage of the signal peptide and subsequent release of mature proteins into the extracellular space. We developed a target-based whole cell assay to screen for potential inhibitors of LepB, the sole signal peptidase in Mycobacterium tuberculosis, using a strain engineered to underexpress LepB (LepB-UE). We screened 72,000 compounds against both the Lep-UE and wild-type (wt) strains. We identified the phenylhydrazone (PHY) series as having higher activity against the LepB-UE strain. We conducted a limited structure-activity relationship determination around a representative PHY compound with differential activity (MICs of 3.0 μM against the LepB-UE strain and 18 μM against the wt); several analogues were less potent against the LepB overexpressing strain. A number of chemical modifications around the hydrazone moiety resulted in improved potency. Inhibition of LepB activity was observed for a number of compounds in a biochemical assay using cell membrane fraction derived from M. tuberculosis. Compounds did not increase cell permeability, dissipate membrane potential, or inhibit an unrelated mycobacterial enzyme, suggesting a specific mode of action related to the LepB secretory mechanism.
journal_name
ACS Infect Disjournal_title
ACS infectious diseasesauthors
Bonnett SA,Ollinger J,Chandrasekera S,Florio S,O'Malley T,Files M,Jee JA,Ahn J,Casey A,Ovechkina Y,Roberts D,Korkegian A,Parish Tdoi
10.1021/acsinfecdis.6b00075subject
Has Abstractpub_date
2016-12-09 00:00:00pages
893-902issue
12issn
2373-8227journal_volume
2pub_type
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