Reconstructing the Antibiotic Pipeline: Natural Alternatives to Antibacterial Agents

The discovery of penicillin led to remarkable progress in the treatment of diseases and far-reaching advancements in novel antibiotics' development and use. However, the uncontrolled use and abuse of antibiotics in subsequent years have led to the emergence of the antimicrobial resistance (AMR) crisis, which now threatens modern medicine. There is an increasing number of emerging and reemerging infectious diseases, which have worsened the state of AMR and pose a serious threat to global health. The World Health Organization (WHO) reports the inadequacy of the drug development pipeline to meet the needs of the pharmaceutical sector in the face of AMR, and this poses a significant challenge in the treatment of diseases. Natural products (NPs) represent a promising group of antibiotic alternatives that can potentially mitigate AMR, as they bypass the pharmacodynamics of traditional antibiotics, thereby making them immune to the mechanisms of AMR. NPs, including plant derivatives, bacteriophages, metals, antimicrobial peptides, enzymes, and immune modulators, as monotherapies or in synergism with existing antibiotics, are gaining attention in a bid to reconstruct the antibiotic pipeline. Harnessing these as antimicrobial agents to curb AMR can help to provide sufficient defence against these infectious pathogens. The current review provides a comprehensive overview of the state of AMR and the potential of the above-mentioned antibiotic alternatives. Additionally, we discuss progress made and research breakthroughs in the application of these alternative therapies in humans, exploring findings from clinical trials and experimental models. The review further evaluates the advancement in technology, interdisciplinary approaches to the formulation and utilisation of NPs, and collaborations in alternative drug development. The research gaps present in this ever-evolving field are highlighted and evaluated together with regulatory issues, safety concerns, and technical difficulties in implementation.