Rising resistance to rifampicin, which blocks bacterial RNA polymerase (RNAP), highlights the need for new tuberculosis treatments. A study published in Nature Microbiology tested a different tactic: pair rifampicin with a second compound that attacks the same transcription pathway at another step. The probe AAP-SO2 binds directly to RNAP at a site distinct from rifampicin and specifically slows the elongation stage of transcription, so the two drugs interrupt different moments in the same process — a tactic the authors call vertical inhibition.
The paper explains why this pairing can counter the common resistance mutation βS450L. That mutation helps bacteria evade rifampicin but also causes RNAP to transcribe more slowly and to stall more often. AAP-SO2 exploits that weakness: it killed the βS450L mutant in culture and removed the mutation from the bacterial population by rendering the bacteria vulnerable to rifampicin once more.
Tests in liquid culture showed additive effects, with each drug contributing without potentiating the other. In a rabbit model that mimics dormant, cluster-like tissue the two drugs were synergistic and together killed far more bacteria; the authors estimate that adding AAP-SO2 increased rifampicin potency substantially in that setting. Because AAP-SO2 was developed as a proof-of-concept probe rather than a drug candidate, the team plans to build a stable derivative and has filed a provisional patent on the dual-inhibition strategy. The work, reported by Rockefeller University and authored by Elizabeth Campbell, Vanisha Munsamy-Govender, Barbara Bosch and Jeremy Rock, reframes TB drug development toward matching companion drugs to specific resistance vulnerabilities.
Difficult words
- RNA polymerase — enzyme that makes RNA from a DNA templateRNAP
- transcription — process of copying DNA information into RNA
- elongation — stage when RNA strand is extended
- mutation — change in DNA sequence in a gene
- exploit — use a weakness or advantage for effectexploits
- synergistic — working together to produce greater combined effect
- potentiate — increase the strength or effect of somethingpotentiating
- vertical inhibition — pairing inhibitors that target different steps in pathway
Tip: hover, focus or tap highlighted words in the article to see quick definitions while you read or listen.
Discussion questions
- What are the potential benefits and challenges of pairing two drugs that target the same pathway at different steps?
- How could matching companion drugs to specific resistance mutations change future tuberculosis treatment strategies?
- The article says AAP-SO2 was a proof-of-concept probe and the team will build a stable derivative. What practical steps and concerns should researchers consider when turning such a probe into a drug?
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