2026-08-10 ロックフェラー大学
＜関連情報＞
- https://www.rockefeller.edu/news/40294-rnap-tb-rna-synthesis/
- https://www.pnas.org/doi/10.1073/pnas.2609228123
- https://www.nature.com/articles/s41564-025-02201-6
RNAポリメラーゼ阻害剤は、ヌクレオチド付加サイクルに不可欠な活性部位の動きを明らかにする RNA polymerase inhibitors reveal active-site motions essential for the nucleotide addition cycle
Yukti Dhingra, Robert Landick, Elizabeth A. Campbell, and Seth A. Darst
Proceedings of the National Academy of Sciences Published:June 30, 2026
DOI:https://doi.org/10.1073/pnas.2609228123
Abstract
The nucleotide addition cycle (NAC) of multisubunit DNA-dependent RNA polymerases (RNAPs) involves coordinated conformational changes in conserved active-site structural elements, including the trigger loop (TL). The TL is open (unfolded) in most RNAP structures but can close (fold) in substrate-bound (post- or pretranslocated) states of the RNAP, promoting catalysis. TL closure has been associated with closure of another conserved structural element, the Rim-Helices/F-loop (RH-FL), but the role of the RH-FL in the NAC is unclear. Antibiotic leads CBR9379 and AAP-SO2 inhibit the Escherichia coli and Mycobacterium tuberculosis RNAPs, respectively, by binding in a pocket formed by the bridge helix and RH-FL. The precise mechanism of action for these inhibitors is yet to be defined. We present cryoelectron microscopy structures showing that both compounds inhibit the RNAP NAC by preventing RH-FL closure, thereby allosterically destabilizing the closed TL. This work reveals a conserved mechanistic principle of RNAP catalysis across all domains of life and provides insight for antibiotic design.
転写共阻害は薬剤耐性進化を変化させ、肉芽腫からの結核菌の除去を促進する Transcription co-inhibition alters drug resistance evolution and enhances Mycobacterium tuberculosis clearance from granulomas
Barbara Bosch,Vanisha Munsamy-Govender,Jansy Sarathy,Mirjana Lilic,Paul Dominic B. Olinares,Kathryn A. Eckartt,Pranav Nalam,Markus Lang,Marcell Simon,Adrian Richter,Jeremy M. Rock & Elizabeth A. Campbell
Nature Microbiology Published:03 December 2025
DOI:https://doi.org/10.1038/s41564-025-02201-6
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, remains the deadliest human pathogen. Treatment is hampered by drug resistance and the persistence of slow-growing or non-replicating populations. Rifampicin, a cornerstone of first-line therapy, inhibits transcription during promoter escape, but resistance mutations undermine efficacy and drive resistance spread. We revisited the transcription cycle as an antibacterial target by characterizing AAP-SO2, an RNA polymerase inhibitor with whole-cell activity against Mtb. AAP-SO2 slows the nucleotide addition cycle, disrupting elongation and termination. Rifampicin-resistant mutations impose fitness costs by perturbing the balance of these steps, creating exploitable weaknesses. Inhibition of transcription with AAP-SO2 reduced the evolution of rifampicin resistance and was especially effective against the most common resistant mutant. Combination treatment with rifampicin and AAP-SO2 synergistically killed non-replicating Mtb in an ex vivo rabbit granuloma model. These findings show that exploiting functional vulnerabilities of the transcription cycle can counter rifampicin resistance and improve clearance of recalcitrant Mtb populations.
