Abstract:
Scientific community is well aware of the fact that pathogenic microorganisms are
becoming resistant to conventional antibiotics at a fast pace. To circumvent this problem,
efforts are now directed towards those molecules which can escape the mechanism of
pathogenic resistance. Antimicrobial peptides are one such group of molecule which has
been serving the purpose of nature’s antibiotic throughout the evolution. In many
organisms they act as a first line of defense against invading microorganisms. However,
their utilization to combat infection outside their natural host requires precise
understanding of their mechanism of action due to their display of toxicity towards
mammalian cells in vitro. Understanding their mechanism of action will assist in design
of novel antimicrobial peptide based therapeutics with cell selective activities as well as
resistance to antibiotic resistant pathogens. Therefore this work is focused towards
identification of those factors which impart toxicity to antimicrobial peptides. This has
been done by selective mutation in the sequence of melittin, magainin 2 and bombolitin
V.
Introductory Chapter 1 presents a brief background of the present work alongwith
the objectives and rationale. Chapter 2 reviews the available literature on antimicrobial
peptides. Chapter 3 describes the materials and methods used to carry out the
investigations. Outcome of our investigation on effect of leucine zipper motif on
biological activity of melittin and its synthetic analogs is presented in Chapter 4.
Chapter 5 deals with the conversion of a non-toxic molecule magainin 2 into toxic one
by introduction of a leucine zipper motif into its sequence. Finally Chapter 6 discusses the regulation of toxicity in bombolitin V by mutation in a conserved leucine zipper
motif, it also present the design of a bombolitin V analog having significantly improved antimicrobial activity with simultaneous reduction of toxicity.
