Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
Project 4
P4
Administrative Core
Systems Biology Core
Clinical Core
Scientific Aims
Overview
Perhaps the greatest barrier to improving tuberculosis (TB) treatment outcomes is the six months of multi- drug therapy that is required to reliably cure a patient with active disease. Lengthy therapy is both costly and leads to poor adherence. This project aims to understand the bacterial factors responsible for lengthy TB treatment, TB treatment failure, and relapse. Mycobacterium tuberculosis (Mtb), the causative agent of TB has developed an exquisite ability to adapt to its environment. Drug treatment can lead to the development of “phenotypically drug-resistant” (i.e. drug tolerant) subpopulations that persist for long periods, as well as atypical very-low level drug resistant mutants (i.e. elevated sub-breakpoint MIC strains) that can eventually relapse despite months of seemingly effective drug treatment. Our overriding hypothesis is that the length of time required to treat TB and the adverse TB outcomes that can occur even with adequate therapy are strongly linked to phenotypic drug resistance and low-level genetic drug resistance mechanisms that can be present in Mtb subpopulation pre-treatment, or that arise during treatment.
Project Leads
Drug Tolerance, Bacterial Heterogeneity and Adverse TB Treatment Outcomes
Key Investigator
Consultant
This project will apply novel tools we have developed, including One-cell Doubling Evaluation of Living Arrays of Mycobacterium (ODELAM), a robotic Transwell Tolerance and Resistance (TTR) system, a complete library of transcription factor inducible (TFI) strains, and constitutively tolerant glpK mutant Mtb strains to investigate the mechanisms that underlie these bacterial states, as well as the heterogeneous expression of tolerance and low level resistance in different Mtb sub-populations.
Scientific Aims
Expanding from well-defined laboratory strains to a diverse collection of well characterized clinical Mtb strains associated with either cure or relapse, we will develop a mechanistic understanding of these still poorly characterized bacterial phenotypes and their role in treatment outcome. These discoveries will lead to important opportunities for developing targeted TB treatments that increase therapeutic success while shortening treatment times. This work will be conducted in three related aims:
1.
Define the links between heterogeneity and phenotypic drug tolerance in Mtb
2.
Determine the role of Mtb phase variation on population heterogeneity, drug tolerance and emergent drug resistance
3.
Assess role(s) of genes, networks, and population heterogeneity in clinical isolates with defined treatment-related phenotypes
References
Transcriptional regulator-induced phenotype screen reveals drug potentiators in Mycobacterium tuberculosis.
Ma S, Morrison R, Hobbs SJ, Soni V, Farrow-Johnson J, Frando A, Fleck N, Grundner C, Rhee KY, Rustad TR, Sherman DR. Nat Microbiol. 2021 Jan;6(1):44-50. doi: 10.1038/s41564-020-00810-x. Epub 2020 Nov 16. PMID: 33199862 Free PMC article.
ODELAM, rapid sequence-independent detection of drug resistance in isolates of Mycobacterium tuberculosis.
Herricks T, Donczew M, Mast FD, Rustad T, Morrison R, Sterling TR, Sherman DR, Aitchison JD. Elife. 2020 May 13;9:e56613. doi: 10.7554/eLife.56613. PMID: 32401195
Transcriptomic Signatures Predict Regulators of Drug Synergy and Clinical Regimen Efficacy against Tuberculosis.
Ma S, Jaipalli S, Larkins-Ford J, Lohmiller J, Aldridge BB, Sherman DR, Chandrasekaran S. mBio. 2019 Nov 12;10(6):e02627-19. doi: 10.1128/mBio.02627-19. PMID: 31719182
Inhibiting the Evolution of Antibiotic Resistance.
Ragheb MN, Thomason MK, Hsu C, Nugent P, Gage J, Samadpour AN, Kariisa A, Merrikh CN, Miller SI, Sherman DR, Merrikh H. Mol Cell. 2019 Jan 3;73(1):157-165.e5. doi: 10.1016/j.molcel.2018.10.015. Epub 2018 Nov 15. PMID: 30449724
Reviews
Genetic Diversity in Mycobacterium tuberculosis Clinical Isolates and Resulting Outcomes of Tuberculosis Infection and Disease.
Peters JS, Ismail N, Dippenaar A, Ma S, Sherman DR, Warren RM, Kana BD. Annu Rev Genet. 2020 Nov 23;54:511-537. doi: 10.1146/annurev-genet-022820-085940. Epub 2020 Sep 14. PMID: 32926793
Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection.
Drain PK, Bajema KL, Dowdy D, Dheda K, Naidoo K, Schumacher SG, Ma S, Meermeier E, Lewinsohn DM, Sherman DR. Clin Microbiol Rev. 2018 Jul 18;31(4):e00021-18. doi: 10.1128/CMR.00021-18. Print 2018 Oct. PMID: 30021818