Advancing Drug Discovery via High‐Throughput Screening of Methylerythritol Phosphate Pathway Enzymes: Strategies and Prospects for Combating Resistance

ABSTRACT

Antibiotic resistance and herbicide resistance have emerged as global threats, urgently necessitating the development of agents with novel modes of action and new targets. The methylerythritol phosphate (MEP) pathway is widely present in bacteria, plants, and apicomplexan parasites, yet absent in mammals. The metabolic products of this pathway are essential for cellular growth and metabolism. Consequently, the key enzymes therein serve as potential targets for developing new antimicrobials and herbicides. Establishing reliable high‐throughput screening (HTS) strategies for enzyme inhibitors is crucial for the rapid discovery of lead compounds, elucidating the interaction mechanisms between inhibitors and target enzymes, and facilitating structure‐based rational drug design. This review systematically summarizes HTS strategies and representative inhibitors for the seven key enzymes in the MEP pathway, based on their biocatalytic reaction principles. The advantages and limitations of various screening methods are analyzed and compared, aiming to provide insights for the development of novel and potent drugs.