Antimicrobial Peptides Derived From Insects Offer a Novel Therapeutic Option to Combat Biofilm: A Review

Abstract

Biofilms form a complex layer with defined structures, that attach on biotic or abiotic surfaces, are tough to eradicate and tend to cause some resistance against most antibiotics. Several studies confirmed that biofilm-producing bacteria exhibit higher resistance compared to the planktonic form of the same species. Antibiotic resistance factors are well understood in planktonic bacteria which is not so in case of biofilm producing forms. This may be due to the lack of available drugs with known resistance mechanisms for biofilms. Existing antibiotics cannot eradicate most biofilms, especially of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). Insects produce complex and diverse set of chemicals for survival and defense. Antimicrobial peptides (AMPs), produced by most insects, generally have a broad spectrum of activity and the potential to bypass the resistance mechanisms of classical antibiotics. Besides, AMPs may well act synergistically with classical antibiotics for a double-pronged attack on infections. Thus, AMPs could be promising alternatives to overcome medically important biofilms, decrease the possibility of acquired resistance and treatment of multidrug-resistant pathogens including ESKAPE. The present review focuses on insect-derived AMPs with special reference to anti-biofilm-based strategies. It covers the AMP composition, pathways and mechanisms of action, the formation of biofilms, impact of biofilms on human diseases, current strategies as well as therapeutic options to combat biofilm with antimicrobial peptides from insects. In addition, the review also illustrates the importance of bioinformatics tools and molecular docking studies to boost the importance of select bioactive peptides those can be developed as drugs, as well as suggestions for further basic and clinical research.

Keywords: ESKAPE; anti-biofilm mechanism of action; antimicrobial peptide; biofilms; insect; molecular docking; multidrug-resistant bacteria; therapeutic and prophylactic strategies.

FIGURE 1

A schematic representation of biofilm-associated human diseases and affected biological systems/organs.

FIGURE 2

Step by step processes toward the development of bacterial biofilms.

FIGURE 3

“The Staphylococcus quorum-sensing system. The agr locus is composed of divergent transcripts designated RNAII and RNAIII, driven by promoters P2 and P3, respectively. The AIP signal is produced from the AgrD precursor, while the membrane-localized enzyme AgrB participates in the maturation and export of the AIP. At a critical threshold concentration, AIP activates the two-component signal transduction system, AgrC–AgrA, and causes the phosphorylation of AgrA. Once phosphorylated, AgrA binds to the P2 and P3 promoter regions, as well as promoters PSM-a and PSM-b, resulting in agr system transcription. RNAIII encodes the delta-toxin encoding gene hld, and 14 stem-loop motifs. These domains regulate the expression of numerous virulence factors. Other regulators (such as SarA, SrrAB, SarR, and SarX) can enhance or inhibit agr activity (Tan et al., 2018).”

FIGURE 4

A systematic approach of bioactive peptide identification and characterization toward development of potent AMPs against biofilm-producing pathogens.

FIGURE 5

Graphical representation of membrane disruption mechanism of peptides against ESKAPE pathogens in both theoretical and computational models (Chen et al., 2018; Silveira et al., 2021).

FIGURE 6

Multi-target mechanism of cecropin A (CecA) action in uropathogenic Escherichia coli (UPEC) biofilms. CecA interacts with LPS to permeabilize bacterial membrane enhancing the diffusion of nalidixic acid (NAL) into the cell. CecA and NLA then bind to different molecular targets in bacteria to disrupt UPEC biofilms (Adopted from https://naturemicrobiologycommunity.nature.com/posts/59576-in-search-of-new-anti-biofilm-agents-from-insects, Mukherjee, 2020).

FIGURE 7

Three-dimensional structure of newly generated ten active antibiofilm peptide derivatives using the PEP-FOLD3 tool. The BIOVIA-Discovery studio visualizer software was used for 3D-visualization in secondary structure format with clean geometry. The backbone protein portion is more fat than other regions, where red color indicated helices regions, gray color indicated coil regions and green color indicated the turn regions of the protein structure.

FIGURE 8

Molecular docking interaction of ten exclusive antibiofilm insect-peptides against the putative biofilm target DNA-binding response regulator/transcriptional factor, LuxR (PDB ID:3B2N) of S. aureus by the peptide docking server, HPEPDOCK. Docking score presented in parentheses with a negative sign and more in negative docking score more in potency according to docking tool.

FIGURE 9

Schematic diagram toward selection and validation of therapeutic peptides using tools of bioinformatics.