Abstract
Marine natural products (MNPs) have been an important and rich source for antimicrobial drug discovery and an effective alternative to control drug resistant infections. Herein, we report bioassay guided fractionation of marine extracts from sponges Lendenfeldia, Ircinia and Dysidea that led us to identify novel compounds with antimicrobial properties. Tertiary amines or quaternary amine salts: aniline 1, benzylamine 2, tertiary amine 3 and 4, and quaternary amine salt 5, along with three known compounds (6–8) were isolated from a crude extract and MeOH eluent marine extracts. The antibiotic activities of the compounds, and their isolation as natural products have not been reported before. Using tandem mass spectrometry (MS) analysis, potential structures of the bioactive fractions were assigned, leading to the hit validation of potential compounds through synthesis, and commercially available compounds. This method is a novel strategy to overcome insufficient quantities of pure material (NPs) for drug discovery and development which is a big challenge for pharmaceutical companies. The antibacterial screening of the marine extracts has shown several of the compounds exhibited potent in-vitro antibacterial activity, especially against methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) values between 15.6 to 62.5 microg mL−1. Herein, we also report structure activity relationships of a diverse range of commercial structurally similar compounds. The structure-activity relationships (SAR) results demonstrate that modification of the amines through linear chain length, and inclusion of aromatic rings, modifies the observed antimicrobial activity. Several commercially available compounds, which are structurally related to the discovered molecules, showed broad-spectrum antimicrobial activity against different test pathogens with a MIC range of 50 to 0.01 µM. The results of cross-referencing antimicrobial activity and cytotoxicity establish that these compounds are promising potential molecules, with a favourable therapeutic index for antimicrobial drug development. Additionally, the SAR studies show that simplified analogues of the isolated compounds have increased bioactivity.
Highlights
Human pathogens are associated with a variety of moderate to severe infections and the recent rise of multi-drug resistant pathogens makes treatment more difficult [1]
Cytotoxicity screens against HepG2, HEK 293, human alveolar epithelial cells (A549) and human leukaemia cells (THP-1) cell lines were performed with concentrations from 500 μg mL−1 to 7.8 μg mL−1 to define the cytotoxicity profile of the most active samples
The results show a general trend of increased activity with increasing chain length of the tertiary amines, as seen in the bioactivity against methicillin-resistant Staphylococcus aureus (MRSA), E. coli and P. aeruginosa (Table 3)
Summary
Human pathogens are associated with a variety of moderate to severe infections and the recent rise of multi-drug resistant pathogens makes treatment more difficult [1]. Natural products continue to offer a productive source of structural diversity and bioactivity and hold the potential for the discovery of new and efficacious antimicrobial drugs [6,7,8,9]. Marine ecosystems have long been a rich source of bioactive natural products in the search for interesting molecules and novel therapeutic agents [6,7,11,12,13]. Many interesting and structurally diverse secondary metabolites have been isolated from marine sources over the last 70 years [8,9,14,15]. The interest in MNPs has continued to grow [8,14,15], spurred in part by the spread of antimicrobial resistant pathogens and the need for new drugs to combat them [6]
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