Targeting Intracellular Pathogenic Bacteria Through N-Terminal Modification of Cationic Amphiphilic Polyproline Helices

Abstract

Intracellular pathogens can thrive within mammalian cells and are inaccessible to many antimicrobial agents. Herein, we present a facile method of enhancing the cell penetrating and antibacterial properties of cationic amphiphilic polyproline helices (CAPHs) with modifications to the hydrophobic moiety at the N-terminus. These altered CAPHs display superior cell penetration within macrophage cells, and in some cases, minimal cytotoxicity. Furthermore, one CAPH, Pentyl-P14 exhibited excellent antibacterial activity against multiple strains of pathogenic bacteria and promoted the clearance of intracellular Shigella within macrophages.

Measurement of Accumulation of Antibiotics toStaphylococcus aureusin Phagosomes of Live Macrophages

“…33 Antimicrobial peptides have also been designed to directly target intracellular bacterial pathogens. [34][35] Together, these efforts highlight the challenges that can arise in the accessibility of antibiotics to phagosomes. We set out to isolate the impact of intracellular residence to the accessibility of antibiotics by systematically determining the permeability of select antibiotics to the cell wall of intracellular S. aureus (Figure 1).…”

“…20 Together, these efforts highlight diverse and promising approaches to targeting intracellular pathogens. 21 We set out to isolate the impact of intracellular residence to the accessibility of antibiotics by systematically determining the permeability of a panel of antibiotics to the cell wall of intracellular S. aureus .…”

Antimicrobial peptides´ immune modulation role in intracellular bacterial infection

“…Within this category, we find CPPs with N-terminal hydrophobic modifications. These altered peptides showed superior cell penetration in macrophages, lower toxicity than in the original peptide, and improved bactericidal activity, where Shigella flexneri clearance is promoted within macrophages ( 101 ).…”

Targeted Drug Delivery Systems for Eliminating Intracellular Bacteria

“…[149] The combination of multiple drugs therapy may reduce the development of drug resistance by decreasing the dosage of a single antibiotic. [150] In addition, it is possible to combine antibiotics and other drugs for the synergistic treatment of drug-resistant intracellular bacteria, such as cellpenetrating peptides (CPPs), [151][152][153][154] anti-inflammatory drugs, [155] and photo/thermodynamic drugs. [156,157] This combination of drugs for efficient clearance of intracellular bacteria is considered a feasible strategy.…”