Inhibition of Pseudomonas aeruginosa and Mycobacterium tuberculosis disulfide bond forming enzymes.
Cristina LandetaLaura McPartlandNgoc Q TranBrian M MeehanYifan ZhangZaidi TanweerShoko WakabayashiJeremy RockTaehyun KimDeepak BalasubramanianRebecca AudetteMelody TooskyJessica PinkhamEric J RubinStephen LoryGerald PierDana BoydJon BeckwithPublished in: Molecular microbiology (2019)
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.
Keyphrases
- mycobacterium tuberculosis
- pseudomonas aeruginosa
- escherichia coli
- biofilm formation
- cystic fibrosis
- pulmonary tuberculosis
- staphylococcus aureus
- acinetobacter baumannii
- antimicrobial resistance
- candida albicans
- transition metal
- emergency department
- cell therapy
- genome wide
- gene expression
- stem cells
- hiv aids
- cell death
- drug resistant
- free survival
- multidrug resistant
- anti inflammatory
- cell proliferation
- adverse drug
- electron transfer