The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent

Abstract

The rise in antimicrobial resistant bacteria threatens the current methods utilized to treat bacterial infections. The development of novel therapeutic agents is crucial in avoiding a post-antibiotic era and the associated deaths from antibiotic resistant pathogens. The human antimicrobial peptide LL-37 has been considered as a potential alternative to conventional antibiotics as it displays broad spectrum antibacterial and anti-biofilm activities as well as immunomodulatory functions. While LL-37 has shown promising results, it has yet to receive regulatory approval as a peptide antibiotic. Despite the strong antimicrobial properties, LL-37 has several limitations including high cost, lower activity in physiological environments, susceptibility to proteolytic degradation, and high toxicity to human cells. This review will discuss the challenges associated with making LL-37 into a viable antibiotic treatment option, with a focus on antimicrobial resistance and cross-resistance as well as adaptive responses to sub-inhibitory concentrations of the peptide. The possible methods to overcome these challenges, including immobilization techniques, LL-37 delivery systems, the development of LL-37 derivatives, and synergistic combinations will also be considered. Herein, we describe how combination therapy and structural modifications to the sequence, helicity, hydrophobicity, charge, and configuration of LL-37 could optimize the antimicrobial and anti-biofilm activities of LL-37 for future clinical use.

Keywords: LL-37; LL-37 derivatives; anti-biofilm peptide; antimicrobial peptide; antimicrobial resistance.

Figure 1

Schematic presenting examples of major cellular resistance mechanisms seen in Gram-negative and Gram-positive bacteria that work to decrease its susceptibility to LL-37. Mechanisms (a–f) are specific to the Gram-negative bacterial envelope. (a) LPS modifications as an example of cell membrane and charge modifications that occur in the outer membrane, (b) efflux pumps, (c) curli production, (d) cholesterol as an example of the incorporation of exogenous molecules into the membrane, (e) the formation of outer membrane vesicles (OMVs) with outer membrane proteins (OMPs) as an example of a component that may be transported via OMVs, and (f) the upregulation of virulence factors that occur in the cytoplasm. Mechanisms (g–j) are specific to the Gram-positive envelope. (g) D-alanination of teichoic acid as an example of cell membrane and charge modifications that occur in the inner membrane, (h) efflux pumps, (i) inhibition of the electron chain (ETC) as an example of a metabolic change in the cell, and (j) the upregulation of virulence factor expression that occur in the cytoplasm.