Abstract:
Management of bacterial infections represents a growing global issue that if left unchecked could threaten the advances of modern medicine. This is largely due to the increasing prevalence of antimicrobial resistance (AMR) within bacteria which is rendering current antibiotic therapies ineffective. The issue of AMR is particularly prevalent in a group of organisms known as the ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. The ESKAPE pathogens are commonly associated with nosocomial infections in hospitals and can cause serious complications in vulnerable patients.
To combat the issue of AMR, previous studies within the Copp group have identified a series of polyamine compounds that possess intrinsic antimicrobial activity and/or the ability to act as antibiotic adjuvants. One initial series of lead compounds were the succinyl primaquine (SPQ) polyamines with the most potent of these compounds being able to potentiate doxycycline activity against P. aeruginosa with an MIC of 6.25 μM. An additional class of polyamine compounds that have also shown potential as antibiotic adjuvants are the indole acrylamides which also displayed an MIC of 6.25 μM when used in combination with doxycycline against P. aeruginosa. To explore the activity of these lead compounds further a series of simplified lipophilic polyamines were chosen to assess the SAR of the original SPQ polyamines and a series of indole acrylamides with substituent variations on the indole ring to see if the activity of these polyamine derivatives could be improved.
A total of 24 simplified lipophilic polyamines and 4 indole acrylamides were synthesised for this work. The biological results of the simplified lipophilic polyamines indicated that longer chain length polyamines generally had greater intrinsic antimicrobial activity when compared with their shorter chain counterparts. Additionally, the 2-naphthyl substituent attached to the core polyamine chain often resulted in the greatest intrinsic and potentiation activity of all the polyamine compounds. These results show that it is possible to simplify the structure of the original SPQ polyamines while still retaining similar biological activity. This opens future exploration of simple polyamine compounds as potential antibiotic adjuvants to be used as treatments of highly resistant pathogens.