ABSTRACT
The escalating crisis of antimicrobial resistance (AMR) underscores the urgent need for novel antimicrobials. One promising strategy is the exploration of structural diversity, as diverse structures can lead to diverse biological activities and mechanisms of action. This review delves into the role of structural diversity in antimicrobial discovery, highlighting its influence on factors such as target selectivity, binding affinity, pharmacokinetic properties, and the ability to overcome resistance mechanisms. We discuss various approaches for exploring structural diversity, including combinatorial chemistry, diversity-oriented synthesis, and natural product screening, and provide an overview of the common mechanisms of action of antimicrobials. We also describe techniques for investigating these mechanisms, such as genomics, proteomics, and structural biology. Despite significant progress, several challenges remain, including the synthesis of diverse compound libraries, the identification of active compounds, the elucidation of complex mechanisms of action, the emergence of AMR, and the translation of laboratory discoveries to clinical applications. However, emerging trends and technologies, such as artificial intelligence, high-throughput screening, next-generation sequencing, and open-source drug discovery, offer new avenues to overcome these challenges. Looking ahead, we envisage an exciting future for structural diversity-oriented antimicrobial discovery, with opportunities for expanding the chemical space, harnessing the power of nature, deepening our understanding of mechanisms of action, and moving toward personalized medicine and collaborative drug discovery. As we face the continued challenge of AMR, the exploration of structural diversity will be crucial in our search for new and effective antimicrobials.
