Navigating the Landscape of Antibiotic Safety: Traditional Approaches and Emerging Strategies to Overcome Host Ribonucleic Acid (RNA) Off-Target Toxicity
Tanya Jamal, Rinni Singh, Mukul Bajpai, Amaan Arif, Ramakrishnan Parthasarathi · ACS Pharmacology & Translational Science · 2025
Antibiotics inhibit bacterial reproduction by blocking cell wall synthesis, protein synthesis, and nucleic acid synthesis as well as altering the cell membrane. Bacteria live in hosts like normal flora. However, they can become pathogenic depending on the pathogen's resistance and the host's susceptibility. A significant gap exists in understanding the off-target toxicity of antibiotics, particularly their unintended interactions with the host nucleic acid machinery. Addressing this is essential for an effective treatment. This review highlights evidence of antibiotics that off-target host RNA, a less-explored but clinically significant phenomenon. The limitations of conventional design within the 3Rs principle are also explored. Evidence from the literature suggests exploiting natural compounds for antibiotics due to their low off-target toxicity. The clinical utility and role of computational tools in speeding up the identification of natural analogues to existing antibiotics are highlighted. The article proposes leveraging natural compounds to mitigate off-target toxicity and to intervene in drug-induced toxicity. Additionally, this emphasizes the importance of interdisciplinary computational methods for identifying analogues. Structural and functional features are prioritized in high-throughput screening to reduce off-target effects, offering a promising approach to drug development.