| dc.description.abstract | Multi-drug resistant (MDR) bacteria or superbugs have become a global threat to human life due to their inherent
resistance to antibiotics. In this context, antimicrobial peptides (AMPs) have emerged as promising alternatives
owing to their unique structural and functional characteristics. In fact, AMPs are less susceptible to bacterial
resistance than traditional antibiotics. Structural insights into these AMPs using NMR spectroscopy have shown
a large correlation between the structure and biological properties of different classes of AMPs, a fact utilised for
designing newer peptide-based antibiotics. Approaches aiming to improve the potency and stability of peptides
necessitate understanding the sequence-structure-function relationship in developing and designing AMP-based
drugs. In contrast to the significant progress over the last decade, particularly regarding AMP optimization,
delivery aspects of AMPs have been less addressed, despite the potential of delivery systems to improve AMP
performance.
This works aims to (i) Characterize, study, and overcome the limitations associated with peptide-based therapy
using the technique of de novo antimicrobial peptide designing, which are effective against plant and animal
disease-causing pathogens. The structural insights of AMPs interacting with bacterial membrane components will
also pave the way to develop novel antimicrobial biopeptides. Initial investigation of the LK series of peptides led
to the designing of short AMPs that would economize the cost and time of synthesis associated with the largescale
synthesis of AMPs to be used as therapeutic molecules. Of the five designed peptides, P2-P6, P4, and P5
were effective against bacterial strains belonging to the ESKAPE group as well as human fungal opportunistic
pathogens. Structural correlation revealed that secondary structures are not a prerequisite for functional attributes
in the case of short peptides. Additionally, the emphasis was made to understand the phenomenon of peptide
synergism by studying the enhanced potency of VG16KRKP and KYE28, 16- and 28-mer de novo designed
peptides, respectively, when used in conjunction with one other. NMR spectroscopy of the complex formed
between these two peptides and their mutated analogs led to discovering an unusual peptide complex,
characterized by the formation of a bulky hydrophobic hub, stabilized by aromatic zippers highlighting this
structure as key for elevating antimicrobial potency of the peptide combination. Furthermore, insights into the
activity of the anti-inflammatory peptide KYE28 and its PEGylated variants have been investigated to correlate
their ability to disintegrate LPS aggregates and the ability of PEGylation for reducing toxicity and proteolytic
susceptibility of AMPs. (ii) Additionally, it also involves probing and studying potential nano-materials as AMP
delivery systems such that AMPs can be used for treating systemic diseases. In this context, it is worth mentioning
that AMPs need to penetrate the cell to target the microbes. Various techniques have been developed for modifying
natural AMPs, making them better suited to cross the cell membrane and get explicitly delivered to the target
bacterial membrane. Gold nanoparticle conjugation and poly (ethylene glycol) conjugation are two such delivery
techniques studied in this work. NMR-based structural insights depicted that both the conjugation techniques
increase the peptides' bioavailability without hampering their functional attributes. | en_US |
