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Title: Development and evaluation of bacterial efflux pump inhibitors
Author: Zhu, Yiling
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Antibiotic resistance is recognised as a significant threat all over the world. The lack of new classes of antibiotics has aggravated the problems. Therefore, novel antimicrobial agents or antimicrobial adjuvants are urgently required. Resistant bacteria have employed a number of mechanisms to protect themselves from being killed by different classes of drugs, one of the most important mechanisms is overexpressed efflux pumps in multidrug-resistant (MDR) bacteria. The idea of developing efflux pump inhibitors (EPIs) that could potentially restore the activity of frontline antibiotics and slow down the progress of developing new resistance, is an attractive approach. This thesis describes the design, chemical synthesis and biological evaluation of a series of quinoline-type compounds as potential EPIs against RND efflux pumps in Gram-negative bacteria. As one of the bacterial species that critically requires the development of new therapeutics (WHO Report 2018), Acinetobacter baumannii was selected as the major species to be studied in this project. Three of its major resistance-nodulation-division (RND) efflux pumps, AdeABC, AdeFGH and AdeIJK, were selected to be investigated and targeted. Although there have been a number of studies of the three efflux pumps, the information on their substrate specificity is unclear. Therefore, the efflux pump activity and the substrate specificity were studied first before screening the novel EPIs. A series of quinoline-based compounds were designed and tested and subsequently modified, with the help of molecular modelling experiments, to understand the differential activity observed as inhibitors against AdeB and AdeG. A total of 38 novel derivatives, including two generations of compounds, were synthesised and tested against a series of A. baumannii strains. Two of the compounds, 4',8'-dimethyl-2'-(2-(pyrrolidin-1-yl) ethoxy)-3,7'-biquinoline (4.11) and 2-((4',8'-dimethyl-[3,7'-biquinolin]-2'-yl)oxy)-N,N-dimethylethan-1-amine (4.25), showed the best efflux pump inhibitory activity from a dye accumulation method (Hoechst assay), as well as to potentiate chloramphenicol by more than 16-fold (from 512 μg/mL to 32 μg/mL) in a AdeG-overexpressing strain, Ab5075-CHL. The results suggest that, to obtain good inhibition against the efflux pump, it is important to have a hetero non-aromatic group (pyrrolidine or dimethyl amine) at the C-2 position, a quinoline at C-7 position, and a C-4 and C-8 methyl group on the core quinoline ring of this series of compounds. Additionally, these quinoline-based compounds were also found to potentiate colistin in a series of colistin susceptible and resistant A. baumannii strains, as well as the colistin resistant E. coli strains. Although their potentiation mechanism has not been identified, they were confirmed neither to depolarize the bacterial membrane in E. coli MG1655 like CCCP, which is known to potentiate colistin, nor inhibit the same efflux pumps responsible for transporting chloramphenicol in A. baumannii strains. Our results show that this series of quinoline-based compounds can specifically inhibit AdeG but not AdeB, and this provides important insights into the structure-activity relationship and the differences between the compounds as efflux pump inhibitors rather than substrates.
Supervisor: Rahman, Khondaker Mirazur Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available