Rapamycin: From Microbial Discovery to Therapeutic Innovations — Advances, Challenges, and Future Prospects

Malak Guermit; Mohamed Marouf Aribi

doi:10.5455/JPPR.20251229122615

Abstract
Abstract
Rapamycin (sirolimus), originally isolated from Streptomyces hygroscopicus, is a macrolide compound that has profoundly influenced modern biomedical research through its inhibition of the mechanistic target of rapamycin (mTOR) pathway. This review synthesizes current knowledge on its microbiological origin, molecular mechanisms, therapeutic applications, and biotechnological optimization, with particular emphasis on recent advances and emerging challenges. A comprehensive analysis of peer-reviewed literature was conducted, focusing on rapamycin biosynthesis, mTOR signaling, clinical uses, and production strategies. Overall, rapamycin and its analogs (rapalogs) demonstrate significant clinical value in areas such as transplantation, oncology, neurodegenerative diseases, and aging research. Recent advances in metabolic engineering, synthetic biology, and nanodelivery systems have markedly enhanced production yields and improved pharmacological performance; however, important limitations persist, including poor solubility, limited bioavailability, metabolic side effects, and concerns regarding long-term safety. Despite these challenges, rapamycin remains a cornerstone molecule bridging microbial natural products and translational medicine, and continued efforts to optimize its production and achieve selective modulation of mTOR signaling will be essential to fully expand its future therapeutic potential.

Key words: Keywords : rapamycin ; mTOR signalling ; Streptomyces;Rapalogs ; pharmacology; biotechnology.