Details

Autor(en) / Beteiligte

• Wynn, Elizabeth A
• Dide-Agossou, Christian
• Reichlen, Matthew
• Rossmassler, Karen
• Al Mubarak, Reem
• Reid, Justin J
• Tabor, Samuel T
• Born, Sarah E M
• Ransom, Monica R
• Davidson, Rebecca M
• Walton, Kendra N
• Benoit, Jeanne B
• Hoppers, Amanda
• Loy, Dorothy E
• Bauman, Allison A
• Massoudi, Lisa M
• Dolganov, Gregory
• Strong, Michael
• Nahid, Payam
• Voskuil, Martin I
• Robertson, Gregory T
• Moore, Camille M
• Walter, Nicholas D
• Stallings, Christina L.

Titel

Transcriptional adaptation of Mycobacterium tuberculosis that survives prolonged multi-drug treatment in mice

Ist Teil von

• mBio, 2023-12, Vol.14 (6), p.e0236323

Ort / Verlag

United States: American Society for Microbiology

Erscheinungsjahr

2023

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• To address the ongoing global tuberculosis crisis, there is a need for shorter, more effective treatments. A major reason why tuberculosis requires prolonged treatment is that, following a short initial phase of rapid killing, the residual withstands drug killing. Because existing methods lack sensitivity to quantify low-abundance mycobacterial RNA in drug-treated animals, cellular adaptations of drug-exposed bacterial phenotypes remain poorly understood. Here, we used a novel RNA-seq method called SEARCH-TB to elucidate the transcriptome in mice treated for up to 28 days with standard doses of isoniazid, rifampin, pyrazinamide, and ethambutol. We compared murine results with SEARCH-TB results during exposure to the same regimen. Treatment suppressed genes associated with growth, transcription, translation, synthesis of rRNA proteins, and immunogenic secretory peptides. Bacteria that survived prolonged treatment appeared to transition from ATP-maximizing respiration toward lower-efficiency pathways and showed modification and recycling of cell wall components, large-scale regulatory reprogramming, and reconfiguration of efflux pump expression. Although the pre-treatment and transcriptomes differed profoundly genes differentially expressed following treatment and were similar, with differences likely attributable to immunity and drug pharmacokinetics in mice. These results reveal cellular adaptations of that withstand prolonged drug exposure demonstrating proof of concept that SEARCH-TB is a highly granular pharmacodynamic readout. The surprising finding that differential expression is concordant and suggests that insights from transcriptional analyses may translate to the mouse. IMPORTANCE A major reason that curing tuberculosis requires prolonged treatment is that drug exposure changes bacterial phenotypes. The physiologic adaptations of that survive drug exposure have been obscure due to low sensitivity of existing methods in drug-treated animals. Using the novel SEARCH-TB RNA-seq platform, we elucidated phenotypes in mice treated for with the global standard 4-drug regimen and compared them with the effect of the same regimen . This first view of the transcriptome of the minority population that withstands treatment reveals adaptation of a broad range of cellular processes, including a shift in metabolism and cell wall modification. Surprisingly, the change in gene expression induced by treatment and was largely similar. This apparent "portability" from to the mouse provides important new context for transcriptional analyses that may support early preclinical drug evaluation.