Bacterial Evolution in Response to the Cancer Chemotherapeutic Drug Bleomycin

Li, Erica (2022) Bacterial Evolution in Response to the Cancer Chemotherapeutic Drug Bleomycin. Doctoral thesis, University of East Anglia.

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The threat of antibiotic resistance has stimulated research into the factors that lead to antibiotic resistance and the spread of antibiotic resistance genes. Recently, it has been shown that exposure to different drugs and disinfectants can select for antibiotic resistance, as many of these agents have antibacterial properties. This includes cancer chemotherapy drugs like bleomycin, used to treat some squamous cell carcinomas and lymphomas. Bleomycin has been shown to have antibacterial activity through damaging bacterial DNA. It has also been found that a bleomycin resistance gene in Enterobacteriaceae is located 3 bp downstream of blaNDM β-lactamase variants that produce the NDM enzyme responsible for conferring resistance to the carbapenem antibiotics. The purpose of this project was to determine whether bleomycin could select for antibiotic resistance via three main mechanisms: identify whether de novo mutations in bacteria that arise after bleomycin exposure may alter bacterial sensitivity to antibiotics, determine whether the bleomycin resistance gene adjacent to the blaNDM β-lactamase may confer a fitness advantage, and whether exposure to bleomycin promotes the movement of mobile genetic elements (MGEs, commonly associated with antibiotic resistance genes). We have found that exposure to bleomycin induces de novo mutations in Escherichia coli in genes that are involved in membrane transporters, biofilm formation and metabolism which may make them less susceptible to the action of antibiotics. Our results indicate that carriage of the bleomycin resistance gene may confer a fitness advantage to bacteria, which may explain its prevalence in existing genome databases and may also indicate its importance in clinical isolates. The movement of MGEs could be tracked using the Hi-C method and combining long-read sequencing can help to overcome the weaknesses associated with short-read sequencing.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Chris White
Date Deposited: 16 Mar 2023 08:41
Last Modified: 16 Mar 2023 08:41

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