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| Type |
Symposium |
| Area |
Current Trends in Biological Chemistry |
| Room No. |
Room 203 |
| Time |
FRI 09:20-: |
| Code |
BIO3-2 |
| Subject |
Modulation of proteolysis as an antibiotic strategy
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| Authors |
Seokhee Kim
Department of Chemistry, Seoul National University, Korea |
| Abstract |
Growing antibiotic resistance demands a new strategy for development of antibiotics. Majority of current antibiotics kill fast-growing bacteria, but show limited effects on a persistent form of bacteria and frequently induce resistance. Protease activators have recently shown to efficiently remove persister cells by uncontrolled proteolysis. Here we explore the activity modulation of a highly conserved periplasmic protease, DegP, as a new antibiotic strategy. Previously, we showed that a mutant form of a small lipoprotein, Lpp(+Leu), which contains an additional leucine at C-terminus, suppressed the lethality of a hyper-active DegP variant, DegP(R207P/Y444A), putatively by inhibiting its activity. Selection of mutant variants reveals that the C-terminal hydrophobic residue is critical for the suppression effect. Surprisingly, Lpp(+Leu) allosterically activates the wild-type DegP at lower concentrations and enhances the substrate affinity. Expression of Lpp(+Leu) in cells reduces the growth fitness at heat-shock stress, indicating that the disruption of the proteolytic balance can inhibit the bacterial growth. We also show that peptide-based tripodal compounds which mimic the C-terminal region of the Lpp(+Leu) trimer can similarly modulate the DegP activity and have the growth inhibition effect. Therefore, we suggest that the tripodal structure with three hydrophobic ends is a novel platform for allosteric effects of DegP or its homologous HtrA proteases, and may be useful in developing new antibiotics.
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| E-mail |
seokheekim@snu.ac.kr |
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121st General Meeting of the KCS