The growing ineffectiveness of common antibiotics against multidrug-resistant pathogens has made antimicrobial resistance (AMR) a serious global health concern. This review emphasizes that natural antibiotics from animals, bacteria, fungi, and plants are worthy alternatives for combating this crisis. Evolutionary pressure has shaped these molecules, leading to antibiotic-resistant bacteria that can withstand single-target synthetic drugs but are vulnerable to multiple attack pathways (e.g., cell wall disruption, protein synthesis inhibition, biofilm interference) from natural compounds. Natural antibiotics are frequently incorporated into treatment strategies or drug-delivery systems for minimizing side effects, reducing doses, and improving their effectiveness. The review discusses recent progress in this field, describing the mechanisms of action of natural antibiotics, their incorporation into several drug-delivery systems, and their ‘omics’-driven discovery to improve production, while expressing the challenges that remain. Extracellular application of these compounds, however, is compromised by their low stability in the extracellular environment; furthermore, formulation advancements, such as nanoparticle encapsulation, have been shown to enhance the bioavailability and activity of these substances. Combining indigenous knowledge and modern scientific advances, natural antibiotics may be developed to fight AMR both as monotherapy and adjuvants in a sustainable way. Leveraging these synergies, alongside the latest advances in research, is key to bridging the antibiotic discovery–resistance gap and may provide a route to clinical translation and global AMR control. The promise of natural antibiotics is clear, but their path to mainstream medicine is fraught with obstacles like reproducibility, standardization, and scalability. It is more realistic to see these substances as powerful complements to existing therapies, not outright replacements. Their true strength is in their ability to interfere with resistance mechanisms and create new possibilities for drug development, positioning them as a vital, though complicated, part of the global effort to combat AMR.
Matei et al. (Mon,) studied this question.