Karakousis Lab

The primary focus of the Karakousis Lab is to understand the molecular basis of persistence and reactivation in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Major research activities include studying the adaptation of M. tuberculosis to stress conditions believed to be important in the infected human host, as well as the phenomenon of phenotypic tolerance to antibiotics. In particular, the regulatory cascade involved in the mycobacterial stringent response is under active investigation. A systems biology-based approach is being used to identify host defense mechanisms responsible for immunological control of M. tuberculosis growth, as well as M. tuberculosis regulatory and metabolic pathways required for bacterial persistence and antibiotic tolerance. The laboratory is also actively investigating the repurposing of various clinically available agents with immune-modulatory properties as adjunctive host-directed therapy, in order to shorten the duration of TB treatment and improve lung pathology. A randomized clinical trial of Statins as Adjunctive Therapy for TB (StAT-TB trial) is investigating the potential adjunctive role of pravastatin in improving microbiological and lung-function outcomes in HIV-infected and uninfected individuals with drug-susceptible, pulmonary TB in South Africa. Finally, molecular assays using blood, sputum, and urine samples are being investigated with the goal of developing rapid, sensitive, and specific point-of-care tests for TB diagnosis and detection of drug resistance.

1. The stringent response factors PPX1 and PPK2 play an important role in Mycobacterium tuberculosis metabolism, biofilm formation, and sensitivity to isoniazid in vivo; Antimicrob Agents Chemother
2. In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D ; Future Microbiol
3. Metformin adjunctive therapy does not improve the sterilizing activity of the first-line antitubercular regimen in mice; Antimicrob Agents Chemother
4. Development of a novel lead that targets M. tuberculosis polyketide synthase 13 ; Cell
5. Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment; Clin Infect Dis
6. Intranasal immunization with DnaK protein induces protective mucosal immunity against tuberculosis in CD4-depleted mice; Front Cell Infect Microbiol
7. Altered Mycobacterium tuberculosis cell wall metabolism and physiology associated with RpoB mutation H526D; Front Microbiol
8. Gene enrichment analysis reveals major regulators of Mycobacterium tuberculosis gene expression in two models of antibiotic tolerance; Front Microbiol
9. Unprecedented in Vitro Antitubercular Activitiy of Manganese(II) Complexes Containing 1,10-Phenanthroline and Dicarboxylate Ligands: Increased Activity, Superior Selectivity, and Lower Toxicity in Comparison to Their Copper(II) Analogs; Front Microbiol

• The role of cell wall lipids in pathogenesis of rifampin-resistant TB
• Quantitative assessment of the tipping point in Mycobacterium tuberculosis transmission and infection
• Statins as adjunctive host-directed therapy for TB
• A novel “shock and kill” strategy for eliminating Mtb persisters in the CD4 T-cell-deficient host
• Immunotherapy Targeting MTB Persisters in the DC-impaired Setting of HIV and TB
• Evaluation of a novel serum biosignature for detecting TB in HIV-infected individuals