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Inhibition of Pseudomonas aeruginosa and Mycobacterium tuberculosis disulfide bond forming enzymes
Author(s) -
Landeta Cristina,
McPartland Laura,
Tran Ngoc Q.,
Meehan Brian M.,
Zhang Yifan,
Tanweer Zaidi,
Wakabayashi Shoko,
Rock Jeremy,
Kim Taehyun,
Balasubramanian Deepak,
Audette Rebecca,
Toosky Melody,
Pinkham Jessica,
Rubin Eric J.,
Lory Stephen,
Pier Gerald,
Boyd Dana,
Beckwith Jon
Publication year - 2019
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.14185
Subject(s) - virulence , pseudomonas aeruginosa , mycobacterium tuberculosis , biology , escherichia coli , microbiology and biotechnology , enzyme , bacteria , cell envelope , biofilm , biochemistry , tuberculosis , genetics , medicine , pathology , gene
Summary In bacteria, disulfide bonds confer stability on many proteins exported to the cell envelope or beyond, including bacterial virulence factors. Thus, proteins involved in disulfide bond formation represent good targets for the development of inhibitors that can act as antibiotics or anti‐virulence agents, resulting in the simultaneous inactivation of several types of virulence factors. Here, we present evidence that the disulfide bond forming enzymes, DsbB and VKOR, are required for Pseudomonas aeruginosa pathogenicity and Mycobacterium tuberculosis survival respectively. We also report the results of a HTS of 216,767 compounds tested against P. aeruginosa DsbB1 and M. tuberculosis VKOR using Escherichia coli cells. Since both P. aeruginosa DsbB1 and M. tuberculosis VKOR complement an E. colidsbB knockout, we screened simultaneously for inhibitors of each complemented E. coli strain expressing a disulfide‐bond sensitive β ‐galactosidase reported previously. The properties of several inhibitors obtained from these screens suggest they are a starting point for chemical modifications with potential for future antibacterial development.