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.
摘要：
不断升级的抗生素耐药性（AMR）危机凸显了对新型抗生素的迫切需求。一个有前途的策略是探索结构多样性，因为不同的结构可以导致不同的生物活性和作用机制。这篇综述探讨了结构多样性在抗菌药物发现中的作用。强调其对目标选择性等因素的影响，结合亲和力，药代动力学特性，以及克服抵抗机制的能力。我们讨论了探索结构多样性的各种方法，包括组合化学，面向多样性的综合，和天然产物筛选，并概述了抗菌药物的常见作用机制。我们还描述了调查这些机制的技术，比如基因组学，蛋白质组学，结构生物学。尽管取得了重大进展,仍然存在一些挑战，包括各种化合物库的合成，活性化合物的鉴定，阐明复杂的作用机制，AMR的出现，以及将实验室发现转化为临床应用。然而,新兴趋势和技术，比如人工智能，高通量筛选，下一代测序，和开源药物发现，为克服这些挑战提供新的途径。展望未来,我们设想了一个令人兴奋的未来，以结构多样性为导向的抗微生物发现，有机会扩大化学空间，利用自然的力量，深化我们对行动机制的理解，走向个性化医疗和合作药物发现。当我们面对AMR的持续挑战时，结构多样性的探索对于我们寻找新的和有效的抗菌药物至关重要。
