Phytochemistry of natural polyamines and their analogues

Abstract

Biofilm formation is a significant mechanism by which pathogens are able to evade the human immune system and to be unresponsive to antimicrobial treatments. Indeed, biofilm formation is a major contributor to antimicrobial resistance (AMR), a current and growing clinical problem around the world. Herein, the synthesis of linear and cyclic polyamines containing different spatial distances between the amino groups were designed on the basis of the chemical structures of certain naturally occurring polyamines. The complete reduction of aliphatic nitrile functional groups to primary amines can be performed via catalytic hydrogenation using Raney nickel catalyst under 1 atm pressure of hydrogen and in basic media. The NMR spectroscopic data of the synthesised polyamines that have not been fully assigned, or indeed are mis-assigned in the literature, were fully and typically unambiguously assigned. Then their biological activities in preventing biofilm formation and for the dispersal of existing biofilms, with and without combination with the antibiotic vancomycin, were investigated. Two novel polyamines 33 and 35 show activity in preventing biofilm formation in NCTC 6571 and MSSA 15981 strains. In the NCTC 6571 strain, each of these two polyamines shows high activity when used in combination with vancomycin achieving higher activity in the killing of bacterial cells inside preformed biofilms than the use of vancomycin alone. Polyamine 49 shows antibacterial activity and prevents biofilm formation in the above two S. aureus strains and in the MRSA 252 strain, and shows high activity in the killing of bacterial cells within preformed NCTC 6571 biofilms in combination with vancomycin. These results are a contribution to the fight against AMR. Whilst simple linear polyamines do not exhibit the biological activity some have claimed in this research area, these three polyamines 33, 35, and 49 certainly do show potential, at least in a bacterial strain dependent manner.

Date of Award	13 Feb 2019
Original language	English
Awarding Institution	University of Bath
Supervisor	Albert Bolhuis (Supervisor) & Ian Blagbrough (Supervisor)