Session Type: ePosters
Session Title: ePosters
Authors(s): H.L. Kan (1), C.W. Tung (2, 3), Y.C. Chen (4), Y.C. Lin (4, 1)
Authors Affiliations(s): (1) Doctoral Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Taiwan, Republic of China, (2) Graduate Institute of Data Science, College of Management, Taipei Medical University, Taiwan, Republic of China, (3) National Institute of Environmental Health Sciences, National Health Research Institutes, Taiwan, Republic of China, (4) School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Taiwan, Republic of China
Background:
Pup-proteasome system (PPS) regulates the degradation of proteins in Mycobacteria. In Mycobacterium tuberculosis, PPS is essential for pathogenesis through maintaining persistence in the macrophages. PafA is the only ligase in the PPS system. The sequence of PafA is highly conserved in Mycobacteriaceae and has no human counterpart. We hypothesized that PafA is an ideal drug target interfering with the intracellular persistency of Mycobacteriaceae. The aim of this study was to identify potential PafA inhibitors.
Methods:We performed a molecular docking on the active pocket of PafA for potential PafA inhibitors. FDA-approved drugs were utilized for screening potential PafA inhibitors. Mycobacterium avium served as a model organism for the in vitro THP-1-macrophages infection model. A known PafA inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was included in all assays as a positive control. Checkerboard method was utilized for evaluating synergistic effect between compounds and rifampin.
Results:We identified and examined 3 potential PafA inhibitors through proteomic analysis. All 3 reduced the numbers of intracellular mycobacterium in the THP-1 macrophages model for about 1 log after 4 days of exposure at the concentration not affecting cell viability. All 3 compounds showed low anti-mycobacterium activity. Only 1 of the chemicals showed additive effects with rifampin.
Conclusions:We identified 3 FDA-approved drugs as PafA inhibitors through molecular docking. These compounds reduced intracellular mycobacterium in THP-1 macrophages. The selected drugs are worth further examined for as a potential adjunct treatment for infections caused by mycobacteria.
Keyword(s): antimycobacterial, PafA, molecular dockingSession Type: ePosters
Session Title: ePosters
Authors(s): H.L. Kan (1), C.W. Tung (2, 3), Y.C. Chen (4), Y.C. Lin (4, 1)
Authors Affiliations(s): (1) Doctoral Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Taiwan, Republic of China, (2) Graduate Institute of Data Science, College of Management, Taipei Medical University, Taiwan, Republic of China, (3) National Institute of Environmental Health Sciences, National Health Research Institutes, Taiwan, Republic of China, (4) School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Taiwan, Republic of China
Background:
Pup-proteasome system (PPS) regulates the degradation of proteins in Mycobacteria. In Mycobacterium tuberculosis, PPS is essential for pathogenesis through maintaining persistence in the macrophages. PafA is the only ligase in the PPS system. The sequence of PafA is highly conserved in Mycobacteriaceae and has no human counterpart. We hypothesized that PafA is an ideal drug target interfering with the intracellular persistency of Mycobacteriaceae. The aim of this study was to identify potential PafA inhibitors.
Methods:We performed a molecular docking on the active pocket of PafA for potential PafA inhibitors. FDA-approved drugs were utilized for screening potential PafA inhibitors. Mycobacterium avium served as a model organism for the in vitro THP-1-macrophages infection model. A known PafA inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was included in all assays as a positive control. Checkerboard method was utilized for evaluating synergistic effect between compounds and rifampin.
Results:We identified and examined 3 potential PafA inhibitors through proteomic analysis. All 3 reduced the numbers of intracellular mycobacterium in the THP-1 macrophages model for about 1 log after 4 days of exposure at the concentration not affecting cell viability. All 3 compounds showed low anti-mycobacterium activity. Only 1 of the chemicals showed additive effects with rifampin.
Conclusions:We identified 3 FDA-approved drugs as PafA inhibitors through molecular docking. These compounds reduced intracellular mycobacterium in THP-1 macrophages. The selected drugs are worth further examined for as a potential adjunct treatment for infections caused by mycobacteria.
Keyword(s): antimycobacterial, PafA, molecular docking
Doctoral Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University.
Session Type: ePosters
Session Title: ePosters
Authors(s): H.L. Kan (1), C.W. Tung (2, 3), Y.C. Chen (4), Y.C. Lin (4, 1)
Authors Affiliations(s): (1) Doctoral Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Taiwan, Republic of China, (2) Graduate Institute of Data Science, College of Management, Taipei Medical University, Taiwan, Republic of China, (3) National Institute of Environmental Health Sciences, National Health Research Institutes, Taiwan, Republic of China, (4) School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Taiwan, Republic of China
Background:
Pup-proteasome system (PPS) regulates the degradation of proteins in Mycobacteria. In Mycobacterium tuberculosis, PPS is essential for pathogenesis through maintaining persistence in the macrophages. PafA is the only ligase in the PPS system. The sequence of PafA is highly conserved in Mycobacteriaceae and has no human counterpart. We hypothesized that PafA is an ideal drug target interfering with the intracellular persistency of Mycobacteriaceae. The aim of this study was to identify potential PafA inhibitors.
Methods:We performed a molecular docking on the active pocket of PafA for potential PafA inhibitors. FDA-approved drugs were utilized for screening potential PafA inhibitors. Mycobacterium avium served as a model organism for the in vitro THP-1-macrophages infection model. A known PafA inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was included in all assays as a positive control. Checkerboard method was utilized for evaluating synergistic effect between compounds and rifampin.
Results:We identified and examined 3 potential PafA inhibitors through proteomic analysis. All 3 reduced the numbers of intracellular mycobacterium in the THP-1 macrophages model for about 1 log after 4 days of exposure at the concentration not affecting cell viability. All 3 compounds showed low anti-mycobacterium activity. Only 1 of the chemicals showed additive effects with rifampin.
Conclusions:We identified 3 FDA-approved drugs as PafA inhibitors through molecular docking. These compounds reduced intracellular mycobacterium in THP-1 macrophages. The selected drugs are worth further examined for as a potential adjunct treatment for infections caused by mycobacteria.
Keyword(s): antimycobacterial, PafA, molecular dockingSession Type: ePosters
Session Title: ePosters
Authors(s): H.L. Kan (1), C.W. Tung (2, 3), Y.C. Chen (4), Y.C. Lin (4, 1)
Authors Affiliations(s): (1) Doctoral Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Taiwan, Republic of China, (2) Graduate Institute of Data Science, College of Management, Taipei Medical University, Taiwan, Republic of China, (3) National Institute of Environmental Health Sciences, National Health Research Institutes, Taiwan, Republic of China, (4) School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Taiwan, Republic of China
Background:
Pup-proteasome system (PPS) regulates the degradation of proteins in Mycobacteria. In Mycobacterium tuberculosis, PPS is essential for pathogenesis through maintaining persistence in the macrophages. PafA is the only ligase in the PPS system. The sequence of PafA is highly conserved in Mycobacteriaceae and has no human counterpart. We hypothesized that PafA is an ideal drug target interfering with the intracellular persistency of Mycobacteriaceae. The aim of this study was to identify potential PafA inhibitors.
Methods:We performed a molecular docking on the active pocket of PafA for potential PafA inhibitors. FDA-approved drugs were utilized for screening potential PafA inhibitors. Mycobacterium avium served as a model organism for the in vitro THP-1-macrophages infection model. A known PafA inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was included in all assays as a positive control. Checkerboard method was utilized for evaluating synergistic effect between compounds and rifampin.
Results:We identified and examined 3 potential PafA inhibitors through proteomic analysis. All 3 reduced the numbers of intracellular mycobacterium in the THP-1 macrophages model for about 1 log after 4 days of exposure at the concentration not affecting cell viability. All 3 compounds showed low anti-mycobacterium activity. Only 1 of the chemicals showed additive effects with rifampin.
Conclusions:We identified 3 FDA-approved drugs as PafA inhibitors through molecular docking. These compounds reduced intracellular mycobacterium in THP-1 macrophages. The selected drugs are worth further examined for as a potential adjunct treatment for infections caused by mycobacteria.
Keyword(s): antimycobacterial, PafA, molecular docking