Antibiotic Potentiation Through Phytochemical-Based Efflux Pump Inhibitors to Combat Multidrug Resistance Bacteria.

BACKGROUND: Antimicrobial resistance development poses a significant danger to the efficacy of antibiotics, which were once believed to be the most efficient method for treating infections caused by bacteria. Antimicrobial resistance typically involves various mechanisms, such as drug inactivation or modification, drug target modification, drug uptake restriction, and drug efflux, resulting in decreased antibiotic concentrations within the cell. Antimicrobial resistance has been associated with efflux Pumps, known for their capacity to expel different antibiotics from the cell non-specifically. This makes EPs fascinating targets for creating drugs to combat antimicrobial resistance (AMR). The varied structures of secondary metabolites (phytomolecules) found in plants have positioned them as a promising reservoir of efflux pump inhibitors. These inhibitors act as modifiers of bacterial resistance and facilitate the reintroduction of antibiotics that have lost clinical effectiveness. Additionally, they may play a role in preventing the emergence of multidrug resistant strains. OBJECTIVE: The objective of this review article is to discuss the latest studies on plant-based efflux pump inhibitors such as terpenoids, alkaloids, flavonoids, glycosides, and tetralones. It highlighted their potential in enhancing the effectiveness of antibiotics and combating the development of multidrug resistance. strains. RESULTS: Efflux pump inhibitors (EPIs) derived from botanical sources, including compounds like lysergol, chanaoclavine, niazrin, 4-hydroxy-α-tetralone, ursolic acid, phytol, etc., as well as their partially synthesized forms, have shown significant potential as practical therapeutic approaches in addressing antimicrobial resistance caused by efflux pumps. Further, several phyto-molecules and their analogs demonstrated superior potential for reversing drug resistance, surpassing established agents like reserpine, niaziridin, etc. strains. CONCLUSION: This review found that while the phyto-molecules and their derivatives did not possess notable antimicrobial activity, their combination with established antibiotics significantly reduced their minimum inhibitory concentration (MIC). Specific molecules, such as chanaoclavine and niaziridin, exhibited noteworthy potential in reversing the effectiveness of drugs, resulting in a reduction of the MIC of tetracycline by up to 16 times against the tested strain of bacteria. These molecules inhibited the efflux pumps responsible for drug resistance and displayed a stronger affinity for membrane proteins. By employing powerful EPIs, these molecules can selectively target and obstruct drug efflux pumps. This targeted approach can significantly augment the strength and efficacy of older antibiotics against various drug resistant bacteria, given that active drug efflux poses a susceptibility for nearly all antibiotics.

Production of Effective Phyto-antimicrobials via Metabolic Engineering Strategies.

The emerging outbreak of infectious diseases poses a challenge and threatens human survival. The indiscriminate use and drying pipelines of antibiotic arsenals have led to the alarming rise of drug-resistant pathogens, projecting a serious concern. The rising antimicrobial resistance and redundancy of antibiotic discovery platforms (ADPs) have highlighted the growing concern to discover new antibiotics, necessitating exploring natural products as effective alternatives to counter drug resistance. Recently, plants have been extensively investigated in search of the "phytotherapeutics", attributed to their potential efficacy and tackling the majority of the drug-resistant mechanisms, including biofilms, efflux pumps, cell communication, and membrane proteins. However, major challenges in geographical fluctuations, low plant concentration, and over-harvestation of natural resources restrict availability and complete utilization of phyto-therapeutics as antimicrobials. Recent advances in scientific interventions have been instrumental in producing novel antimicrobials via metabolic engineering approaches in plant systems. The progress in plant genome editing, pathway reconstitution, and expression has defined new paradigms in the successful production of antimicrobials in the post-antibiotic era. The thematic review discusses the existing and emerging significance of phytotherapeutics in tackling antimicrobial resistance and employing metabolic engineering approaches. The prevailing scenario of antimicrobial resistance and the mechanisms, the traditional and modern drug-discovery approaches in addressing antimicrobial resistance, emphasizing advances in metabolic engineering approaches for antimicrobial production, and the plausible solutions for tackling drug-resistant pathogens, forms the key theme of the article.

Inhibiting Bacterial Drug Efflux Pumps via Phyto-Therapeutics to Combat Threatening Antimicrobial Resistance.

Antibiotics, once considered the lifeline for treating bacterial infections, are under threat due to the emergence of threatening antimicrobial resistance (AMR). These drug-resistant microbes (or superbugs) are non-responsive to most of the commonly used antibiotics leaving us with few treatment options and escalating mortality-rates and treatment costs. The problem is further aggravated by the drying-pipeline of new and potent antibiotics effective particularly against the drug-resistant strains. Multidrug efflux pumps (EPs) are established as principal determinants of AMR, extruding multiple antibiotics out of the cell, mostly in non-specific manner and have therefore emerged as potent drug-targets for combating AMR. Plants being the reservoir of bioactive compounds can serve as a source of potent EP inhibitors (EPIs). The phyto-therapeutics with noteworthy drug-resistance-reversal or re-sensitizing activities may prove significant for reviving the otherwise fading antibiotics arsenal and making this combination-therapy effective. Contemporary attempts to potentiate the antibiotics with plant extracts and pure phytomolecules have gained momentum though with relatively less success against Gram-negative bacteria. Plant-based EPIs hold promise as potent drug-leads to combat the EPI-mediated AMR. This review presents an account of major bacterial multidrug EPs, their roles in imparting AMR, effective strategies for inhibiting drug EPs with phytomolecules, and current account of research on developing novel and potent plant-based EPIs for reversing their AMR characteristics. Recent developments including emergence of in silico tools, major success stories, challenges and future prospects are also discussed.