# Natural Products as Potentiators of β-Lactam Antibiotics: A Review of Mechanisms, Advances, and Future Directions

## TL;DR

This review explores how natural products can enhance the effectiveness of β-lactam antibiotics to combat antibiotic resistance.

## Contribution

The paper systematically reviews mechanisms and strategies of natural products as antibiotic adjuvants, highlighting future directions.

## Key findings

- Natural products like flavonoids and clavulanic acid can inhibit β-lactamases and efflux pumps.
- Multi-omics and AI are proposed to accelerate the discovery of effective antibiotic adjuvants.
- In vitro and in vivo methods are essential for evaluating synergistic effects of natural products.

## Abstract

This review focuses on the research progress on natural products as β-lactam antibiotic adjuvants, aiming to address the escalating challenge of antibiotic resistance, particularly the inactivation of antibiotics caused by β-lactamases. The article provides an in-depth analysis of the mechanisms by which plant-derived (e.g., flavonoids, tannins, phenolics, terpenoids, and alkaloids) and microbial-derived (e.g., clavulanic acid, fungal metabolites, bacteriophages) natural products enhance antimicrobial efficacy. Key potentiation strategies discussed include efflux pump inhibition, membrane permeability alteration, biofilm disruption, PBP2a inhibition, and direct β-lactamase inhibition. Additionally, the review outlines in vitro methods (e.g., dilution and checkerboard assays) and in vivo models (e.g., mouse infection models) used to assess synergistic effects. It also addresses major challenges in identifying active compounds, elucidating mechanisms of action, and pharmacokinetic characterization. Looking forward, the article highlights the potential of multi-omics approaches, artificial intelligence, and nanotechnology to overcome existing bottlenecks, providing novel strategies for the development of effective and safe antibiotic adjuvants. These advances are expected to provide both theoretical insights and practical guidance for combating antibiotic-resistant bacterial infections.