Fluoroquinolone Resistance in Escherichia coli: Interplay of Mechanisms, Dose Selection and Targets for Suppression
| dc.contributor.advisor | Tam, Vincent H. | |
| dc.contributor.advisor | Knoll, Brian J. | |
| dc.contributor.committeeMember | Zechiedrich, E. Lynn | |
| dc.contributor.committeeMember | Lewis, Russell E. | |
| dc.contributor.committeeMember | Hu, Ming | |
| dc.creator | Singh, Renu | |
| dc.date.accessioned | 2013-02-06T18:09:06Z | |
| dc.date.available | 2013-02-06T18:09:06Z | |
| dc.date.created | December 2010 | |
| dc.date.issued | 2010-12 | |
| dc.date.updated | 2013-02-06T18:09:08Z | |
| dc.description.abstract | Antibiotic resistance emergence is a blooming health problem. The interaction between the pathogen, antimicrobial agent and the host presents a complex challenge. Attempts to suppress the emergence of resistance have been relatively unsuccessful. One of the reasons for this could be a gap in our understanding of how bacteria deal with these agents. Our studies were focused to understand the intricacies involved in the resistance development process under antibiotic selective pressure and to find strategies to suppress antibiotic resistance emergence. Bacteria have a natural tendency to form spontaneous mutants. It is likely that a high inoculum may harbor pre-existing mutants, which could be selectively amplified if the dose exposure is sub-optimal. Using a high inoculum of Escherichia coli, we demonstrated that an optimal dose exposure of moxifloxacin could be selected to suppress resistance. Even at a low inoculum, multiple bacterial mechanisms, such as target site mutations and efflux pump overexpression can lead to resistance. The SOS response system is one of the mechanisms inducing mutations by the derepression of gene involved in error prone replication. We investigated the effect of recA deletion (the sensor of the SOS system) on the emergence of resistance in E. coli. Our results suggest that apart from MIC reduction, recA deletion/inhibition could be beneficial in delaying the fluoroquinolone resistance emergence in E. coli. Efflux pump overexpression is another common mechanism implicated in antibiotic resistance. Although efflux pumps confer low-level resistance, we demonstrated that efflux mechanisms facilitate acquisition of target site mutations that eventually lead to high-level resistance. In the wild-type E. coli, efflux pump overexpression (acrAB) preceded the acquisition of target site mutations. Experiments conducted with efflux pump deleted (ΔacrAB) strain delayed the emergence of resistance suggesting that the inhibition of AcrAB efflux pump could be a robust strategy for slowing the development of resistance in clinically important Gram-negative bacteria. Our results from these studies have added to the present understanding of the antibiotic resistance development process and have highlighted the importance of efflux pumps in facilitating the development of high-level fluoroquinolone resistance in E. coli. | |
| dc.description.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/10657/ETD-UH-2010-12-82 | |
| dc.language.iso | eng | |
| dc.rights | The author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Fluoroquinolones | |
| dc.subject | E. coli | |
| dc.subject | Efflux pumps | |
| dc.subject | PK/PD | |
| dc.subject | Levofloxacin | |
| dc.subject | AcrAB-TolC | |
| dc.subject.lcsh | Communicable diseases | |
| dc.title | Fluoroquinolone Resistance in Escherichia coli: Interplay of Mechanisms, Dose Selection and Targets for Suppression | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| thesis.degree.college | College of Pharmacy | |
| thesis.degree.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| thesis.degree.discipline | Pharmacology | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.major | Infectious disease | |
| thesis.degree.name | Doctor of Philosophy |