Superfast Evolution of Bacterial Resistance to Beta-Lactam Antibiotics Mediated by Bacterial DNA Recombination

Zhang, Le

Superfast Evolution of Bacterial Resistance to Beta-Lactam Antibiotics Mediated by Bacterial DNA Recombination

Zhang, Le

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Publication Type:: Thesis
Issue Date:: 2020

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Field	Value	Language
dc.contributor.author	Zhang, Le
dc.date.accessioned	2021-03-19T01:16:00Z
dc.date.available	2021-03-19T01:16:00Z
dc.date.issued	2020
dc.identifier.uri	http://hdl.handle.net/10453/147374
dc.description	University of Technology Sydney. Faculty of Science.	en_US
dc.description.abstract	The emergence of antibiotic resistance is a global problem. Many studies show that sub-lethal concentration of antibiotic exposure or transit exposure to antibiotics can induce the formation of persistence or tolerance; whereas, cyclic exposure (usually 8-17 days) of antibiotics promotes the accumulation of bacterial adaptive mutations in persisters towards the subsequent evolution of resistance. However, the antibiotics induce mutagenesis that damage bacterial DNA has been poorly understood. Notably, the induction of SOS response has always been believed to aid bacterial propagation defense against antibiotic lethality, which requires the activation of SOS-promoting 𝘳𝘦𝘤𝘈. A recent study implicated the essential role of RecA in the evolution of resistance to fluoroquinolones antibiotics, but it is unclear whether this is a conserved mechanism of resistance in response to different antibiotic classes. RecA has been considered as a drug target to suppress the induction of SOS response towards the evolution of resistance caused by the broad-spectrum fluoroquinolone antibiotics. Here, we report that single exposure of β-lactam antibiotics can trigger a superfast evolution of resistance in 𝘳𝘦𝘤𝘈 deletion 𝘌. 𝘤𝘰𝘭𝘪 strain, independent to the SOS response. This type of single exposure causes gene mutations on an uncharacterized gene 𝘱𝘪𝘯𝘙, and its encoded protein may be involved in DNA recombination. Moreover, single or intermittent treatment of β-lactam antibiotics fails to induce the resistance in the 𝘱𝘪𝘯𝘙 deletion 𝘌. 𝘤𝘰𝘭𝘪 strain. This work highlights the antagonistic role among DNA recombinases in the emergence of antibiotic resistance, and demonstrates that loss of 𝘳𝘦𝘤𝘈 increases the rate of resistance to β-lactam antibiotics, but PinR is likely to be a novel drug target.	en_US
dc.format	Thesis (PhD)
dc.language.iso	en	en_US
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/147374/2/02whole.pdf
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	au.edu.uts.lib/ppc
dc.rights	info:eu-repo/semantics/openAccess
dc.title	Superfast Evolution of Bacterial Resistance to Beta-Lactam Antibiotics Mediated by Bacterial DNA Recombination	en_US
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

The emergence of antibiotic resistance is a global problem. Many studies show that sub-lethal concentration of antibiotic exposure or transit exposure to antibiotics can induce the formation of persistence or tolerance; whereas, cyclic exposure (usually 8-17 days) of antibiotics promotes the accumulation of bacterial adaptive mutations in persisters towards the subsequent evolution of resistance. However, the antibiotics induce mutagenesis that damage bacterial DNA has been poorly understood. Notably, the induction of SOS response has always been believed to aid bacterial propagation defense against antibiotic lethality, which requires the activation of SOS-promoting 𝘳𝘦𝘤𝘈. A recent study implicated the essential role of RecA in the evolution of resistance to fluoroquinolones antibiotics, but it is unclear whether this is a conserved mechanism of resistance in response to different antibiotic classes. RecA has been considered as a drug target to suppress the induction of SOS response towards the evolution of resistance caused by the broad-spectrum fluoroquinolone antibiotics. Here, we report that single exposure of β-lactam antibiotics can trigger a superfast evolution of resistance in 𝘳𝘦𝘤𝘈 deletion 𝘌. 𝘤𝘰𝘭𝘪 strain, independent to the SOS response. This type of single exposure causes gene mutations on an uncharacterized gene 𝘱𝘪𝘯𝘙, and its encoded protein may be involved in DNA recombination. Moreover, single or intermittent treatment of β-lactam antibiotics fails to induce the resistance in the 𝘱𝘪𝘯𝘙 deletion 𝘌. 𝘤𝘰𝘭𝘪 strain. This work highlights the antagonistic role among DNA recombinases in the emergence of antibiotic resistance, and demonstrates that loss of 𝘳𝘦𝘤𝘈 increases the rate of resistance to β-lactam antibiotics, but PinR is likely to be a novel drug target.

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http://hdl.handle.net/10453/147374