Antimicrobial peptide therapy for tuberculosis infections

Abstract: Tuberculosis is a communicable disease that persists as a second leading cause for death, by an infectious agent. Several reasons contribute to this issue to this, of which an upsurge in antibiotic resistance is of top concern. Resistance patterns in the form of mono or multidrug resistance was reported to most clinical therapies at our disposal. This thesis aims to address this issue by studying a novel antimicrobial peptide named NZX as a potential drug candidate in the tuberculosis treatment regimen. Mycobacterium tuberculosis, the tuberculosis pathogen is made up of a unique cell wall that renders it resistant to most compounds tested. We set out to identify the membrane interactive potential of NZX using artificial liposomes and live bacteria. The peptide appeared to interact with inner membrane of live mycobacteria by a pull and aggregate mechanism, eventually disrupting the cell integrity. A similar aggregation pattern was observed for liposomes as well as insertion into the membrane core was demonstrated. Antimicrobial peptides are known to possess multiactivity mode of mechanism. To understand this, we investigated internal targets through a proteomics study. This led to the identification of essential protein targets such as chaperonins 60 kDa and elongation factor EF-Tu involved in bacterial growth and maintenance. Together, these findings displayed NZX’s multifaceted activity against mycobacteria. The lack of mutants from resistance development studies for NZX could be asserted to their multiactivity feature. Evidence of the therapeutic potential of NZX as an antimicrobial agent was explored. NZX displayed a wide range of activity when tested against a few clinically isolated nontuberculosis mycobacteria species and drug-resistant Staphylococcus aureus. The effect of drug-to-drug interactions were observed from an in vivo and in vitro standpoint and the peptide portrayed an additive effect with ethambutol, however, remained indifferent with other drug combinations. NZX retained its stability and antimicrobial property despite exposure to proteolytic molecules and human serum respectively. Directed therapy of NZX was performed by loading NZX onto nanoparticles and was found to be effectual for intracellular therapy. Moreover, nanoparticle loaded NZX exhibited better antimicrobial activity in primary macrophages. The data presented here shows cumulative evidence on NZX as a prospective candidate against mycobacterial infections.