Combating Antimicrobial Resistance: Innovative Strategies Using Peptides, Nanotechnology, Phages, Quorum Sensing Interference, and CRISPR-Cas Systems

Abstract

Antimicrobial resistance (AMR) has emerged as one of the most pressing global health challenges of our time. Alarming projections of increasing mortality from resistant infections highlight the urgent need for innovative solutions. While many candidates have shown promise in preliminary studies, they often encounter challenges in terms of efficacy and safety during clinical translation. This review examines cutting-edge approaches to combat AMR, with a focus on engineered antimicrobial peptides, functionalized nanoparticles, and advanced genomic therapies, including Clustered Regularly Interspaced Short Palindromic Repeats-associated proteins (CRISPR-Cas systems) and phage therapy. Recent advancements in these fields are critically analyzed, with a focus on their mechanisms of action, therapeutic potential, and current limitations. Emphasis is given to strategies targeting biofilm disruption and quorum sensing interference, which address key mechanisms of resistance. By synthesizing current knowledge, this work provides researchers with a comprehensive framework for developing next-generation antimicrobials, highlighting the most promising approaches for overcoming AMR through rational drug design and targeted therapies. Ultimately, this review aims to bridge the gap between experimental innovation and clinical application, providing valuable insights for developing effective and resistance-proof antimicrobial agents.

Keywords: antimicrobial peptides; biofilm disruption; combination therapies; drug delivery systems; multidrug resistance.

Figure 2

Metabolic pathway of folate synthesis in bacteria, highlighting the target enzymes of inhibitors DHPS (dihydropteroate synthase), DHFS (dihydrofolate synthase), and DHFR (dihydrofolate reductase). Adapted by Pradhan and Sinha [59]. Created in BioRender. Souto, E. (2025) https://BioRender.com/a81d0mj (accessed on 19 July 2025).

Figure 5

Chemical structures of compounds with anti-quorum sensing activity. (a) Chalcone derivative 1-(5-chlorothiophen-2-yl)-5-[4-(dimethylamino)phenyl]prop-2-en-1-one (designated as DC05). Adapted from Nayak and collaborators [161]. (b) Selected cationic amino acids with anti-quorum sensing activity against P. aeruginosa and C. violaceum. Adapted from Abinaya and collaborators [167]. (c) Structural variations of five naturally occurring halogenated furanones (compounds 1–5) from the marine macroalga Delisea pulchra and a synthetic derivative (compound 8). Adapted from Manefield and collaborators [169]. All chemical structures were drawn using ACD/ChemSketch (Freeware).

Figure 6

Chemical structures of some phytochemicals with demonstrated anti-QS activity: (a) naringenin; (b) oroidin; (c) salicylic acid; (d) ursolic acid; (e) cinnamaldehyde; and (f) methyl eugenol. Source: PubChem (https://pubchem.ncbi.nlm.nih.gov/, accessed on 25 June 2025).

Figure 1

Mechanisms of bacterial antibiotic resistance. Created by Biorender.com.

Figure 3

Recent technology strategies against multidrug-resistant bacteria. Academic Individual License granted to UCD/E. B. Souto OBRSS Research Support Scheme (AIUCD241022-cd0d). Created with BioRender.com.

Figure 4

CRISPR-Cas antimicrobial strategies: (A) Gene editing in MRSA: CRISPR-Cas9 targets the mecA gene (encoding PBP2a), restoring β-lactam susceptibility. (B) Phage delivery: Engineered bacteriophages deliver CRISPR-Cas to selectively eliminate pathogens (e.g., E. coli, P. aeruginosa) while preserving microbiota. (C) Biofilm disruption: CRISPRi silences quorum sensing genes in P. aeruginosa, inhibiting biofilm matrix formation. Created in BioRender. Souto, E. (2025) https://BioRender.com/a2dd7iy (accessed on 19 July 2025).