Inhibition of Pseudomonas aeruginosa and Mycobacterium tuberculosis disulfide bond forming enzymes
| Autor: | Laura McPartland, Jessica T. Pinkham, Cristina Landeta, Dana Boyd, Rebecca E Audette, Deepak Balasubramanian, Eric J. Rubin, Taehyun Kim, Ngoc Quang Tran, Brian M. Meehan, Yi-Fan Zhang, Jeremy M. Rock, Stephen Lory, Zaidi Tanweer, Shoko Wakabayashi, Gerald B. Pier, Melody Toosky, Jon Beckwith |
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| Rok vydání: | 2018 |
| Předmět: |
medicine.drug_class
Virulence Factors Antibiotics Virulence Biology medicine.disease_cause Microbiology Article Mycobacterium tuberculosis Small Molecule Libraries 03 medical and health sciences Mice Bacterial Proteins medicine Escherichia coli Animals Disulfides Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences 030306 microbiology Pseudomonas aeruginosa Membrane Proteins biology.organism_classification High-Throughput Screening Assays Mice Inbred C57BL Enzyme chemistry Female Cell envelope Bacteria |
| Zdroj: | Molecular microbiology. 111(4) |
| ISSN: | 1365-2958 |
| Popis: | 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. coli dsbB 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. |
| Databáze: | OpenAIRE |
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