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Review
. 2012 Jul;7(7):823-37.
doi: 10.2217/fmb.12.56.

Discovery and Development of SQ109: A New Antitubercular Drug With a Novel Mechanism of Action

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Free PMC article
Review

Discovery and Development of SQ109: A New Antitubercular Drug With a Novel Mechanism of Action

Katherine A Sacksteder et al. Future Microbiol. .
Free PMC article

Abstract

Existing drugs have limited efficacy against the rising threat of drug-resistant TB, have significant side effects, and must be given in combinations of four to six drugs for at least 6 months for drug-sensitive TB and up to 24 months for drug-resistant TB. The long treatment duration has led to increased patient noncompliance with therapy. This, in turn, drives the development of additional drug resistance in a spiral that has resulted in some forms of TB being currently untreatable by existing drugs. New antitubercular drugs in development, particularly those with mechanisms of action that are different from existing first- and second-line TB drugs, are anticipated to be effective against both drug-sensitive and drug-resistant TB. SQ109 is a new TB drug candidate with a novel mechanism of action that was safe and well tolerated in Phase I and early Phase II clinical trials. We describe herein the identification, development and characterization of SQ109 as a promising new antitubercular drug.

Figures

Figure 1
Figure 1. WHO estimated TB incidence rates, 2011
Reproduced with permission from [101].
Figure 2
Figure 2. Process to identify new drug candidate, SQ109, from a focused combinatorial library of 1,2-ethylenediamine small-molecule compounds
Data taken from [46,54].
Figure 3
Figure 3. SQ109 mechanism of action
The figure depicts stylized components of the cell wall, while primarily focusing on TMM and TDM. Hypothetical or proposed steps are indicated by gray lines, and question marks in parentheses represent hypothetical proteins/enzymes not yet identified. The inset legend represents the shapes used to depict the components shown. Note that the diagram is not to scale and does not include detailed structures or all components of the mycobacterial cell wall. MmpL3, the target of SQ109, is proposed to be the ABC transporter (red circle). TDM: Trehalose dimycolate; TMM: Trehalose monomycolate. Adapted with permission from [24].
Figure 4
Figure 4. SQ109 tissue levels after oral administration to mice for 28 days
SQ109 at 10 mg/kg; drug levels were measured 1 h after the last administration of the drug. Reproduced with permission from [60].
Figure 5
Figure 5. SQ109 activity compared with ethambutol in the standard drug regimen
Estimation of CFUs (white colonies of Mycobacterium tuberculosis on plates of 7H10 agar incubated at 37°C, 5% CO2 in a humidified incubator for 3 weeks) in undiluted lung homogenates of Mycobacterium tuberculosis-infected mice treated for 6 weeks with standard of care TB drugs (right plate: ~568 CFU) or a combination containing SQ109 in place of EMB (left plate: ~18 CFU). EMB: Ethambutol; INH: Isoniazid; PZA: Pyrazinamide; RIF: Rifampicin. Data taken from [76].
Figure 6
Figure 6. Treatment of mice with bedaquiline alone or incombination with SQ109 and/or pyrazinamide
After 3 weeks of infection with Mycobacterium tuberculosis, female C57BL/6 mice were either treated with nothing (infected control, ten mice) for 3 months or with one of the described regimens in groups of 30 mice/regimen. Drug concentrations were: bedaquiline, 25 mg/kg; SQ109, 25 mg/kg; PZA, 150 mg/kg. Mice were evaluated for CFU/lung at 2 and 3 months. After 3 months of drug therapy, all control mice were dead, and lungs of ten mice in all groups were harvested and plated to evaluate CFU. Lung tissues from all drug-treated groups were culture-negative (no CFU). After therapy termination, 20 additional mice of each drug-treated group were rested (no treatment) for 3 months. Lungs were extracted, homogenized and plated undiluted on 7H10 agar for 3 weeks. CFU/lung 1 × 100 means no detected CFU (limit of detection = 1 bacterium/ml of undiluted lung homogenate). PZA: Pyrazinamide.

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