α,ω-Diacyl-Substituted Analogues of Natural and Unnatural Polyamines: Identification of Potent Bactericides That Selectively Target Bacterial Membranes

Abstract

In this study, α-ω-disubstituted polyamines exhibit a range of potentially useful biological activities, including antimicrobial and antibiotic potentiation properties. We have prepared an expanded set of diarylbis(thioureido)polyamines that vary in central polyamine core length, identifying analogues with potent methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Acinetobacter baumannii and Candida albicans growth inhibition properties, in addition to the ability to enhance action of doxycycline towards Gram-negative bacterium Pseudomonas aeruginosa. The observation of associated cytotoxicity/hemolytic properties prompted synthesis of an alternative series of diacylpolyamines that explored aromatic head groups of varying lipophilicity. Examples bearing terminal groups each containing two phenyl rings (15a–f, 16a–f) were found to have optimal intrinsic antimicrobial properties, with MRSA being the most susceptible organism. A lack of observed cytotoxicity or hemolytic properties for all but the longest polyamine chain variants identified these as non-toxic Gram-positive antimicrobials worthy of further study. Analogues bearing either one or three aromatic-ring-containing head groups were either generally devoid of antimicrobial properties (one ring) or cytotoxic/hemolytic (three rings), defining a rather narrow range of head group lipophilicity that affords selectivity for Gram-positive bacterial membranes versus mammalian. Analogue 15d is bactericidal and targets the Gram-positive bacterial membrane.

Structure–Activity Relationship Studies of Indolglyoxyl-Polyamine Conjugates as Antimicrobials and Antibiotic Potentiators

“…The susceptibility of bacterial strains S. aureus (ATCC 25923), E. coli (ATCC 25922) and P. aeruginosa (ATCC 27853) to antibiotics and compounds was determined according to previously reported protocols [ 17 ]. Additional antimicrobial evaluation against MRSA (ATCC 43300) and C. albicans (ATCC 90028) was undertaken at the Community for Open Antimicrobial Drug Discovery at The University of Queensland (Australia) according to their standard protocols as reported previously [ 17 , 26 ].…”

“…Antibiotic enhancing activities were determined according to previously reported protocols [ 14 , 17 ].…”

“…A component of the structure–activity relationship yet to be addressed in this compound series is the effect, if any, of variation in the polyamine (PA) chain length on intrinsic antimicrobial, antibiotic enhancement and cytotoxicity/hemolysis biological activities. Previous studies investigating disubstituted polyamine-bearing arylacyl [ 17 ] head groups identified that changes in the chain length of the core polyamine fragment can lead to wide variation in antimicrobial and/or antibiotic enhancing properties. Herein we report details on the synthesis of a new set of indolglyoxyl-polyamine conjugates that vary in substitution at the 5- and 7- positions on the indole ring and that vary in polyamine chain length, and the abilities of these analogues to exhibit intrinsic antimicrobial properties and to potentiate the activity of doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa .…”

Investigation of Naphthyl–Polyamine Conjugates as Antimicrobials and Antibiotic Enhancers

“…We recently reported the synthesis and antimicrobial evaluation of a set of α,ω-diacylaryl substituted polyamine analogues, of which examples 5–7 ( Figure 2 ) are representative [ 27 ].…”

“…Any analogues with cLogP greater than 9–10 appear to breach a ‘second hydrophobicity threshold’ [ 28 ], leading to greater disruption of mammalian membranes and inherent toxicity. Mechanism of action studies carried out on the diaryl-analogue 6 identified it as a strong disruptor of bacterial cell membranes and to be bactericidal [ 27 ], making it a good starting point for further optimization.…”