Molecular Redesign of Phenylalanine-Arginine-β-Naphthylamide and Biocompatible Efflux Pump Inhibitors for Multidrug Resistant Bacteria: Current Trends and Future Prospects

Abstract

The escalating global crisis of antimicrobial resistance necessitates innovative therapeutic strategies, with efflux pump inhibitors emerging as a promising avenue to restore the efficacy of existing antibiotics. Multidrug-resistant Gram-negative bacteria pose a significant global health threat, largely due to the pervasive role of multidrug efflux pumps in mediating antibiotic resistance by extruding various antimicrobial compounds. This review aimed to explore the current literature on restoring antimicrobial efficacy against formidable Gram-negative bacteria by the strategic molecular redesign of phenylalanine-arginine-β-naphthylamide and other biocompatible efflux pump inhibitors to circumvent resistance mechanisms. The current published literature findings and evidence on molecular redesign of phenylalanine-arginine-β-naphthylamide and biocompatible efflux pump inhibitors were synthesized from authentic sources. Findings revealed that a distinctive architecture of Gram-negative bacterial envelopes, characterized by an outer membrane, periplasmic space, and inner membrane, presents a formidable barrier to antibiotic entry, with efflux pumps serving as a primary resistance mechanism. Specifically, Resistance-Nodulation-Division efflux pumps, prominent in Gram-negative bacteria, actively transport a broad spectrum of structurally diverse antibiotics out of the cell, contributing significantly to intrinsic and acquired multidrug resistance. This efflux mechanism, a natural process for substrate removal in both prokaryotic and eukaryotic cells, renders many antibiotics ineffective by actively expelling them from the bacterial cytoplasm. Consequently, the development of efflux pump inhibitors has emerged as a crucial strategy to re-sensitize resistant bacteria to existing antibiotics, thereby enhancing therapeutic outcomes against persistent infections.