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Elucidating the role of the two-component systems QseBC and PmrAB in mediating resistance to positively charged antibiotics

dc.creatorHurst, Melanie Noelle 2022
dc.description.abstractAntibiotic resistance is a growing global health threat. According to the CDC, nearly 2.8 million drug-resistant infections occur every year, killing 35,000 people annually. While research has focused on the acquisition and spread of mobile genetic elements, chromosomally encoded mechanisms have also contributed to resistance. One type of resistance, heteroresistance, describes a population in which a sub-population has some genetic or phenotypic change that allows them to survive an antibiotic assault. This change can be the result of a gene amplification mutation, or stochasticity in gene expression. This thesis describes heteroresistance in uropathogenic E.coli (UPEC) driven by the PmrAB and QseBC two-component systems and by changes in metabolism and acid resistance genes. It delves into the mechanism in which these two-component systems confer resistance to polymyxins through the use of ChIP- on-chip and RNA sequencing. This work assigns a novel role to the response regulator QseB. This response regulator acts as a controller of metabolism, directly targeting several systems that feed into the TCA cycle. When the data is combined from all sources, a clear picture emerges of metabolic control that is necessary during LPS modifications. Interestingly, this metabolic control appears to hinge on glutamate and oxoglutarate balance. Therefore, we interrogated the role that a third system, KguRS may play in mediating resistance to positively charged antibiotics. KguRS is a sensor of oxoglutarate. In a survival assay against polymyxin B, we found KguRS to be necessary for mounting a response. We then set out to characterize the system through various methods. Together this data creates a picture in which PmrAB, QseBC, and KguRS are important for mounting resistance to positively charged antibiotics and can drive heteroresistance in non-inducing conditions.
dc.subjectantibiotic resistance
dc.subjecttwo-component systems
dc.titleElucidating the role of the two-component systems QseBC and PmrAB in mediating resistance to positively charged antibiotics
dc.type.materialtext Interactions University Graduate School
dc.contributor.committeeChairKarijolich, John

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