Editorial - Mechanisms of Action of Natural Products Against Resistant Microorganisms

Abstract

Antimicrobial resistance is a major public health threat driving the search for new therapeutic options. This special collection compiles studies on natural products active against resistant microorganisms. The results show that natural compounds rarely act on a single target, instead affecting metabolic pathways, cell wall integrity, and enhancing antibiotic and antifungal activity. Alkaloids disrupt energy metabolism and protein function, plant extracts act synergistically with antibiotics, and bee-derived products function as antimicrobial adjuvants. Overall, these findings highlight the translational potential of natural products in addressing antimicrobial resistance, supporting future antimicrobial drug development and innovation strategies in the fight against resistance globally.

Introduction

Antimicrobial resistance (AMR) is now recognized as one of the most urgent global health threats, steadily undermining the effectiveness of conventional antibiotics and contributing to increased morbidity and mortality worldwide. ¹ The rapid expansion of multidrug resistant pathogens has intensified the search for alternative and complementary therapeutic approaches. ² In this context, natural products continue to represent a valuable reservoir of antimicrobial agents due to their structural diversity and broad biological activities. ³ Unlike many conventional antibiotics that act through a single defined target, these compounds often interfere with microbial survival through multiple mechanisms, including membrane disruption, interference with metabolic and biosynthetic pathways, and enhancement of antibiotic efficacy. ⁴

This special collection, “Mechanisms of Action of Natural Products Against Resistant Microorganisms,” brings together studies that move beyond isolated activity reports to provide a more integrated view of how these compounds function at molecular and cellular levels. Importantly, the collection distinguishes itself by not only compiling recent findings but also by highlighting how convergent patterns across different natural products may inform future antimicrobial strategies and drug development efforts.

Contributions of Collections

This special collection brings together studies that collectively illustrate the diversity and translational potential of natural products as antimicrobial agents. Rather than acting through a single pathway, these compounds target multiple bacterial and fungal processes, ranging from central metabolism to cell wall homeostasis and drug potentiation.

Liao et al demonstrated that chelerythrine, a benzophenanthridine alkaloid isolated from Zanthoxylum species, exerts potent activity against methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) of 19.54 mg/L. Proteomic analysis revealed broad metabolic disruption, with 36 proteins persistently downregulated, particularly those involved in glycolysis, the tricarboxylic acid cycle, and amino acid metabolism. This reduction in key enzymes indicates impaired energy production and suggests that chelerythrine induces metabolic collapse. ⁵ Complementing this mechanism, the compound also promotes site specific deamidation of the major autolysin Atl at Asn617, impairing its muramidase activity and disrupting cell wall remodeling. Together, these findings highlight a multi target mode of action that combines metabolic interference with post translational modification of essential proteins. ⁶

While some natural products act directly on microbial physiology, others enhance the efficacy of existing antibiotics. In this context, Bezerra et al showed that honey, fermented pollen extract, and beeswax extract from Melipona rufiventris lack strong intrinsic antibacterial activity (MIC ≥1024 µg/mL) against multidrug-resistant strains. However, they significantly reduced the MICs of conventional antibiotics. Notably, gentamicin and β-lactam antibiotics showed improved activity across S. aureus, Escherichia coli, and Pseudomonas aeruginosa. These findings suggest a potential role for these products as antibiotic adjuvants, possibly through mechanisms such as enzyme inhibition or increased membrane permeability. ⁷

A similar potentiating effect was observed in plant derived extracts. Hailu et al evaluated Hagenia abyssinica and Vernonia amygdalina, identifying polar phytochemicals including flavonoids, tannins, and alkaloids as key contributors to antibacterial activity. Methanol and acetone extracts showed the strongest effects, in some cases comparable to ciprofloxacin, supporting their traditional medicinal use and reinforcing the importance of extraction methods in bioactivity studies. ⁸

Expanding on combination strategies, Mgbeahuruike et al ⁹ investigated Salix aurita and Salix myrsinifolia in conjunction with tetracycline and ciprofloxacin against Bacillus cereus. Both extracts enhanced antibiotic efficacy at low concentrations, with S. aurita producing particularly strong synergistic effects, including up to a 32-fold reduction in MIC. These results underscore the value of plant-derived compounds in restoring or amplifying antibiotic activity.

Finally, antifungal modulation was explored using the essential oil of Rhabdocaulon lavanduloides. Although the oil exhibited only a fungistatic effect on Candida species, its interaction with fluconazole was strain dependent, showing synergy in Candida tropicalis but possible antagonism in Candida albicans. Molecular docking suggested that the major compound shares a similar binding profile with fluconazole, indicating a potential role in modulating antifungal drug activity rather than acting as a standalone agent. ¹⁰

Conclusion

This collection underscores the versatility of natural products as both antimicrobial agents and enhancers of existing therapies. The studies show that these compounds act through multiple pathways, including metabolic disruption, post translational modification, and antibiotic potentiation, highlighting their potential to address antimicrobial resistance from different angles. Despite these advances, key challenges remain. A clearer understanding of how these compounds act at the molecular level is still needed, and reported synergistic effects with conventional antibiotics must be rigorously validated under clinically relevant conditions to ensure reproducibility. Most importantly, translating these findings into practical therapies remains a major hurdle, requiring advances in pharmacokinetics and safety assessment. By linking functional insights with therapeutic potential, this collection moves the field beyond isolated observations toward a more integrated perspective and helps define priorities for future research aimed at developing effective and clinically relevant strategies to combat antimicrobial resistance.