Addressing Antimicrobial Resistance by Repurposing Polyphenolic Phytochemicals with Novel Antibacterial Potential

Multi-drug resistance (MDR) is a burgeoning health problem in the clinical practice of infectious diseases. The widespread and indiscriminate use of broad-spectrum antibiotics has significantly increased antimicrobial resistance (AMR). According to current estimates, an annual death toll of 700,000 people has been attributed to antibiotic resistant infections and approximately 10 million lives may be at risk by 2050 if no novel chemotherapeutic measures are taken. The emergence of MDR and drug resistance pathogens combined with limited therapeutic efficacies and clinical uses of existing antimicrobial agents, including antibacterial antibiotics, pose a significant challenge to public health. Therefore, the discovery of novel and effective antimicrobial therapeutics that fight against MDR bacterial infections are urgently needed. Phytochemicals or plant-based natural products have been a potential source of drug candidates for human diseases for many years. The modern drug discovery process involves screening of active compounds for their development for successful molecule/drug candidates based on specific biological target(s). Drug repurposing (also referred to as repositioning) is the process of finding new potential uses/targets of existing drugs, and it has gained significant attention in recent years. It offers significant advantages over traditional drug discovery programs in terms of attrition rate, time, and cost of development. This strategy employs a combined approach of medicinal chemistry and bioinformatics in search of new drug candidates with the application of high-throughput in silico and cell-based screening against a novel drug target. However, the emergence of MDR has been attributed to different biological processes, such as damage to the bacterial cell membrane and suppression of virulence factors , including inhibition of the activity of bacterial enzymes, such as expolysaccharides, and bacterial biofilm formation. Moreover, oxidative stress induced by a reactive oxygen species plays a crucial role in modulating these mechanisms of drug resistance in pathogenic bacteria. According to recent studies, many phytochemicals , including polyphenolic compounds, have been reported to exert their antibacterial potential against MDR pathogenic bacterial species, such as Staphylococcus aureus , methicillin-resistant S. aureus , and Pseudomonas aeruginosa , by interfering with the above mechanisms of drug resistance. In this chapter, the antibacterial activities of polyphenolic phytochemicals and flavonoids (such as catechins, epigallocatechin gallate, quercetin, apigenin, luteolin, and genistein) with antioxidant potential against possible molecular targets will be reviewed to explore their therapeutic benefits and/or further development as novel drug candidates for MDR bacterial infections.