Antimicrobial Peptides: A Promising Solution to the Rising Threat of Antibiotic Resistance

Abstract

The demand for developing novel antimicrobial drugs has increased due to the rapid appearance and global spread of antibiotic resistance. Antimicrobial peptides (AMPs) offer distinct advantages over traditional antibiotics, such as broad-range efficacy, a delayed evolution of resistance, and the capacity to enhance human immunity. AMPs are being developed as potential medicines, and current computational and experimental tools aim to facilitate their preclinical and clinical development. Structural and functional constraints as well as a more stringent regulatory framework have impeded clinical translation of AMPs as possible therapeutic agents. Although around four thousand AMPs have been identified so far, there are some limitations of using these AMPs in clinical trials due to their safety in the host and sometimes limitations in the biosynthesis or chemical synthesis of some AMPs. Overcoming these obstacles may help to open a new era of AMPs to combat superbugs without using synthetic antibiotics. This review describes the classification, mechanisms of action and immune modulation, advantages, difficulties, and opportunities of using AMPs against multidrug-resistant pathogens and highlights the need and priorities for creating targeted development strategies that take into account the most cutting-edge tools currently available. It also describes the barriers to using these AMPs in clinical trials.

Keywords: microorganisms; multi-drug resistance; peptide antibiotics; peptide design; therapeutics.

Figure 1

(A) Sources of AMPs identified by January 2024. The information was collected using APD. (B) Published reports on antimicrobial peptides from 2013 to 2023, including journal articles, books and documents, clinical reports, meta-analyses, and reviews. Report calculations were carried out by searching in PubMed with the help of key words “antimicrobial peptides” and “AMP”.

Figure 1

(A) Sources of AMPs identified by January 2024. The information was collected using APD. (B) Published reports on antimicrobial peptides from 2013 to 2023, including journal articles, books and documents, clinical reports, meta-analyses, and reviews. Report calculations were carried out by searching in PubMed with the help of key words “antimicrobial peptides” and “AMP”.

Figure 2

The natural sources of AMPs and their site-specific activities against different microorganisms. The figure shows different natural sources of AMPs and their antimicrobial activity against bacteria, viruses, fungi, and parasites. The bolded texts indicate the target sites of the AMPs, and the AMPs mentioned with each site indicate the AMPs that act against that specific site.

Figure 3

Mechanisms of action of AMPs. The left portion of the figure indicates the direct killing mechanism of AMPs, whereas the right side indicates the immune modulation mechanism of AMPs. In direct killing, AMPs either disrupt the pathogens’ cell membrane, or inhibit the internal functions like protein synthesis and cell wall formation, leading to cell death. Immune modulation is an indirect killing mechanism where the AMPs provoke the immune system to take actions against the target pathogen.

Figure 4

Phylogenetic analysis of 99 anti-MRSA antimicrobial peptides (AMPs) identified from different natural sources. Sources include different bacteria, fungi, animals, and plants. A total of 99 anti-MRSA AMP sequences were retrieved from the APD and Xuan et al. [125]. The phylogeny tree was constructed based on multiple sequence alignment using MEGA-11. The evolutionary history was inferred by using the Maximum Likelihood method and JTT matrix-based model. The tree with the highest log likelihood (−6284.65) is shown. Initial tree(s) for the heuristic search were obtained automatically by applying Neighbor-Join and BioNJ algorithms to a matrix of pairwise distances estimated using the JTT model, and then selecting the topology with superior log likelihood value. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site.

Figure 5

Schematic diagram of AMPs in combating superbugs. (A) The classification of AMPs based on antimicrobial activity. (B) The classification of AMPs based on synthesis. (C) Complications of using AMPs in clinical trials. (D) Designing AMPs for enhancing efficacy.