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theses

Antibiotic resistance poses a significant challenge in anti-infective therapy. There are several mechanisms involved in antibiotic resistance with efflux being a major determinant. Overcoming efflux will allow for the reintroduction of old antibiotics and prevent the development of resistance to new antibiotics. Several bacterial efflux pump inhibitors (EPIs) have been discovered, but none of these compounds have been FDA-approved for use in humans. There is a need for a systematic study of some of these inhibitors to gain a better understanding of their structure activity relationship (SAR). This work focuses on the SAR studies conducted on two classes of known EPI inhibitors. Analogues of aryl piperazines (biphenyl piperazines and naphthalene amines) were synthesized and tested for their EPI activity. None of the compounds in this series exhibited EPI activity and thus no further exploration was done on their SAR. Structurally simpler analogues of phenylalanine-arginine β-naphthylamide (PAβN) were also designed and an SAR study conducted on the three different scaffolds proposed. The three scaffolds include the “normal” amides, the “reverse” amides and the secondary amine series. Although these scaffolds exhibited some similarities in their SAR, there were some differences. In all cases, the 1,5-diphenylpentane core was the preferred substituent on the right hand side of the molecules. For the left hand side, diaminopentane was the preferred substituent. Further studies revealed that N5 substitution was detrimental to EPI activity. The “reverse” amides had better activity when compared against their analogous “normal” amides. The data indicated that a bis-alkylaryl was necessary for activity and that there was preference for the aryl to be hydrophobic. A methylene insertion in the reverse amides series gave a compound that caused 512-fold reduction in the minimum inhibitory concentration (MIC) of clarithromycin (PAβN, the historical EPI standard offered a 4-fold reduction in MIC). The amine analogues also offered some active compounds with one of these compounds causing a 128-fold reduction in the MIC of clarithromycin. (These tests were done in E. coli). Some success was achieved in P. aeruginosa; two compounds when independently co-administered with levofloxacin resulted in a 32-fold decrease in the MIC of levofloxacin.

ETD_7118

Ph.D.

Includes bibliographical references

by Gifty Ayensu Blankson

doi:10.7282/T3FT8P5Z

ETD doctoral

The author owns the copyright to this work.