Bioinspired Design of Precision Antimycobacterial Peptides

Restricted (Penn State Only)
Author:
Mongia, Agustey Shikhar
Area of Honors:
Biomedical Engineering
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Scott H Medina, Thesis Supervisor
  • Justin Lee Brown, Honors Advisor
  • Pak Kin Wong, Faculty Reader
Keywords:
  • Antimicrobial Peptides
  • Membrane Disruption
  • Mycobacterium
  • Tuberculosis
Abstract:
The rapid and continuous emergence of multidrug resistant bacteria threatens to erase the gains antibiotics have made in modern medicine. Pathogens responsible for human infections, particularly of the respiratory tract (e.g. pneumonia, tuberculosis), are highly adept at mutating to develop drug resistance mechanisms. The development of new antimicrobial tools with unique mechanisms of action combats the growing threat of drug-resistant superinfections. One class of such agents is antimicrobial peptides (AMPs), which potently kill drug-resistant bacteria through physical disruption of their membranes, a mechanism not shared by conventional antibiotics. Importantly, these membrane-active sequences permeabilize bacterial cell walls to enhance diffusion of antibiotics and thereby enhance their potency through synergistic mechanisms. This study focuses on the development of a new AMP with potent and selective action against Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), and exploring its mechanism of action. In addition, this study examines the synergistic activity of the peptide with clinically approved antibiotics against both drug-sensitive and antibiotic-resistant respiratory pathogens. The peptide studied was shown to target Mycobacterium strains, specifically M. tuberculosis and M. smegmatis, as opposed to gram-positive and gram-negative bacteria. Through biophysical assays, it was shown that this peptide is capable of disrupting mycolic acid cord factor lipids, the common virulent factor in Mycobacterium strains. In combination with current clinically approved antibiotics, the peptide showed synergistic and additive effects in both mycobacterial strains. Further studies were completed to test toxicity in macrophages and human controls. These results may enable the development of targeted, narrow-spectrum antimicrobial strategies capable of killing bacterial pathogens, without disrupting commensal microbial communities important for preventing drug-resistance and opportunistic infections.