Browsing by Author "Spathelf, Barbara Marianne"
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- ItemQualitative structure-activity relationships of the major tyrocidines, cyclic decapeptides from Bacillus aneurinolyticus(Stellenbosch : University of Stellenbosch, 2010-03) Spathelf, Barbara Marianne; Rautenbach, Marina; University of Stellenbosch. Faculty of Science. Dept. of Biochemistry.ENGLISH ABSTRACT: The need for alternative or supplementary treatments due to the global problem of microbial resistance towards conventional antimicrobials may be met by the development of novel drugs based on antimicrobial peptides. The antimicrobial peptides of interest to this study were the tyrocidines, cyclic decapeptides produced by Bacillus aneurinolyticus. Although these antimicrobial peptides were the first natural antibiotic to be discovered though a systematic search for antibacterial compounds, information regarding their bioactivity, structure-activity relationships, determinants of bioactivity and mode of action is limited. The aim of this study was to investigate the antibacterial and antiplasmodial activity, as well as to identify determinants of bioactivity modulation, of the natural tyrocidine library. The study indicated that the tyrocidines exhibit significant activity toward Gram-positive bacteria, notably Listeria monocytogenes, and the intraerythocytic parasite, Plasmodium falciparum. Both the antilisterial and antiplasmodial activity was found to be highly dependent on peptide identity and self-assembly. The antilisterial activity of the tyrocidines was shown to be associated with increased self-assembly within a membrane-like environment, which suggested that formation of lytic complexes within the bacterial membrane may play a crucial role in tyrocidine activity. In contrast to the observations for antilisterial activity, the antiplasmodial activity of the tyrocidines was shown to be associated with reduced self-assembly within a membrane-like environment, which suggested that the antiplasmodial activity of the tyrocidines is mediated by a mechanism other than the formation of lytic complexes within the target cell membrane. In addition to the influence of peptide identity and self-assembly, the bioactivity of the tyrocidines was found to be highly sensitive to environmental conditions, notably the presence of calcium. The antilisterial activity, as well as the mode of action, of the tyrocidines was also found to be highly sensitive to tyrocidine-Ca2+ complexation and the concomitant induction of higher-order structures. Tyrocidine-Ca2+ complexation was shown to greatly enhance antilisterial activity and change the mechanism of action from a predominantly membranolytic to an alternative, non-lytic mode of action. The results of this investigation suggest that the alternative mode of tyrocidine activity may be related to complexation with Ca2+. It is hypothesised that such complexation may either (1) promote tyrocidine-DNA complexation, and thus inhibition of transcription and/or replication; or (2) interfere with Ca2+ homeostasis, and thus influence vital cell functions. Overall, it may be hypothesised that tyrocidine activity and mode of action is modulated by a critical play-off between self-assembly, cation-complexation and membrane-interaction. As these modulators of activity are highly dependent on tyrocidine sequence/structure, the wide variety of tyrocidines found in the natural complex may allow for optimal interaction with and activity toward a variety of microbes.