The Expanding Role of Indole Scaffolds in Combating Antimicrobial Resistance

The global escalation of antimicrobial resistance poses a critical threat to public health, emphasizing the need for innovative therapeutic scaffolds with novel mechanisms of action. Among various heterocyclic frameworks, the indole nucleus has attracted significant attention due to its structural versatility and extensive pharmacological profile. The discussion systematically examines diverse biological targets, including bacterial cell wall biosynthesis, FtsZ-mediated cytokinesis, DNA gyrase, dihydrofolate reductase, glutathione S-transferase, and CYP51 enzymes. For each target, recent synthetic analogs, their mechanistic implications, and structure-activity relationships are examined to highlight the molecular determinants responsible for enhanced efficacy and selectivity. Classical and contemporary synthetic strategies, such as the Fischer, Bartoli, and Madelung methods, as well as metal-catalyzed cyclisation methods, are outlined to provide a foundation for rational drug design. Furthermore, molecular docking and structure-based drug design studies are reviewed to correlate binding affinities with observed bioactivities. The inclusion of FDA-approved indole-containing drugs and ongoing clinical evaluations underscores the translational relevance of this scaffold. Overall, this review accentuates the versatility of the indole core as a privileged pharmacophore and its promise in the development of next-generation antimicrobial agents capable of overcoming multidrug resistance. Continued efforts to optimize indole hybrids and elucidate their mechanistic pathways are anticipated to yield potent, safe, and clinically viable therapeutics.