Combined experimental and theoretical study of Type-II toxin-antitoxin system response to antibiotics
Апстракт
Bacterial Type-II toxin-antitoxin (TA) systems, including kacAT in Klebsiella pneumoniae,
respond to antibiotics. We investigated kacAT’s regulation relevant to antibiotic
persistence, which refers to the survival of antibiotic exposure by dormant bacterial cells.
Elevated toxin levels may induce dormancy. KacAT complex binds and represses the
kacAT promoter cooperatively, leading to highly non-linear negative feedback. Antibiotics
increase transcription of the kacA and kacT genes by inducing KacA degradation and
consequently reducing the KacA:KacT ratio. Our model reproduced experimental findings,
explaining increased kacAT transcription and reduced [KacA]:[KacT] ratio. Interestingly,
KacAT overexpression induces antibiotic stress tolerance, while deleting kacAT has no
effect, which our model can also explain. KacAT, therefore, cannot induce spontaneous (in
the absence of antibiotics) persister formation. Earlier theoretical models, which predicted
spontaneous persistence i...n Type-II TA systems, assumed the cooperative action of
multiple TA systems. Our bioinformatics analysis, however, reveals a limited occurrence
of multiple TA instances within clades and that cross-talk between clades is disfavored.
These challenges the assumption of cooperativity in TA action, possibly explaining the
absence of spontaneous persister generation in kacAT.
Кључне речи:
type II toxin-antitoxin systems / antibiotic persistence / systems biology / nonlienar dynamics / gene expression regulation / bioinformaticsИзвор:
4th Belgrade Bioinformatics Conference, 2023, 4, 77-77Издавач:
- Belgrade : Institute of molecular genetics and genetic engineering
Финансирање / пројекти:
- This work was supported by the Science and Technology Commission of Shanghai Municipality (grants no. 19430750600 and 19JC1413000)
- National Natural Science Foundation of China (grant no. 32070572)
- Medical Excellence Award funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University (grant no. XK2019025)
- Science Fund of the Republic of Serbia (grant no. 7750294, q-bioBDS)
Напомена:
- Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 2023
Колекције
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - CONF AU - Ilić, Bojana AU - Đorđević, Marko AU - Ou, Hong-Yu PY - 2023 UR - https://belbi.bg.ac.rs/ UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2017 AB - Bacterial Type-II toxin-antitoxin (TA) systems, including kacAT in Klebsiella pneumoniae, respond to antibiotics. We investigated kacAT’s regulation relevant to antibiotic persistence, which refers to the survival of antibiotic exposure by dormant bacterial cells. Elevated toxin levels may induce dormancy. KacAT complex binds and represses the kacAT promoter cooperatively, leading to highly non-linear negative feedback. Antibiotics increase transcription of the kacA and kacT genes by inducing KacA degradation and consequently reducing the KacA:KacT ratio. Our model reproduced experimental findings, explaining increased kacAT transcription and reduced [KacA]:[KacT] ratio. Interestingly, KacAT overexpression induces antibiotic stress tolerance, while deleting kacAT has no effect, which our model can also explain. KacAT, therefore, cannot induce spontaneous (in the absence of antibiotics) persister formation. Earlier theoretical models, which predicted spontaneous persistence in Type-II TA systems, assumed the cooperative action of multiple TA systems. Our bioinformatics analysis, however, reveals a limited occurrence of multiple TA instances within clades and that cross-talk between clades is disfavored. These challenges the assumption of cooperativity in TA action, possibly explaining the absence of spontaneous persister generation in kacAT. PB - Belgrade : Institute of molecular genetics and genetic engineering C3 - 4th Belgrade Bioinformatics Conference T1 - Combined experimental and theoretical study of Type-II toxin-antitoxin system response to antibiotics EP - 77 SP - 77 VL - 4 UR - https://hdl.handle.net/21.15107/rcub_imagine_2017 ER -
@conference{ author = "Ilić, Bojana and Đorđević, Marko and Ou, Hong-Yu", year = "2023", abstract = "Bacterial Type-II toxin-antitoxin (TA) systems, including kacAT in Klebsiella pneumoniae, respond to antibiotics. We investigated kacAT’s regulation relevant to antibiotic persistence, which refers to the survival of antibiotic exposure by dormant bacterial cells. Elevated toxin levels may induce dormancy. KacAT complex binds and represses the kacAT promoter cooperatively, leading to highly non-linear negative feedback. Antibiotics increase transcription of the kacA and kacT genes by inducing KacA degradation and consequently reducing the KacA:KacT ratio. Our model reproduced experimental findings, explaining increased kacAT transcription and reduced [KacA]:[KacT] ratio. Interestingly, KacAT overexpression induces antibiotic stress tolerance, while deleting kacAT has no effect, which our model can also explain. KacAT, therefore, cannot induce spontaneous (in the absence of antibiotics) persister formation. Earlier theoretical models, which predicted spontaneous persistence in Type-II TA systems, assumed the cooperative action of multiple TA systems. Our bioinformatics analysis, however, reveals a limited occurrence of multiple TA instances within clades and that cross-talk between clades is disfavored. These challenges the assumption of cooperativity in TA action, possibly explaining the absence of spontaneous persister generation in kacAT.", publisher = "Belgrade : Institute of molecular genetics and genetic engineering", journal = "4th Belgrade Bioinformatics Conference", title = "Combined experimental and theoretical study of Type-II toxin-antitoxin system response to antibiotics", pages = "77-77", volume = "4", url = "https://hdl.handle.net/21.15107/rcub_imagine_2017" }
Ilić, B., Đorđević, M.,& Ou, H.. (2023). Combined experimental and theoretical study of Type-II toxin-antitoxin system response to antibiotics. in 4th Belgrade Bioinformatics Conference Belgrade : Institute of molecular genetics and genetic engineering., 4, 77-77. https://hdl.handle.net/21.15107/rcub_imagine_2017
Ilić B, Đorđević M, Ou H. Combined experimental and theoretical study of Type-II toxin-antitoxin system response to antibiotics. in 4th Belgrade Bioinformatics Conference. 2023;4:77-77. https://hdl.handle.net/21.15107/rcub_imagine_2017 .
Ilić, Bojana, Đorđević, Marko, Ou, Hong-Yu, "Combined experimental and theoretical study of Type-II toxin-antitoxin system response to antibiotics" in 4th Belgrade Bioinformatics Conference, 4 (2023):77-77, https://hdl.handle.net/21.15107/rcub_imagine_2017 .