| 2017 | NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans. | Sci Rep | During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2 mice with TB to monotherapy before or after establishment of human-like pathology. Isoniazid induced a drug-tolerant persister population only when necrotic lesions were present. Rifapentine was more potent than rifampin prior to development of human-like pathology and equally potent thereafter, in agreement with recent clinical trials. Pretomanid, Delamanid and the pre-clinical candidate BTZ043 were bactericidal independent of pulmonary pathology. Linezolid was bacteriostatic in TB-infected Nos2 mice but significantly improved lung pathology. Hypoxic necrotizing lesions rendered moxifloxacin less active. In conclusion, Nos2 mice are a predictive TB drug development tool owing to their consistent development of human-like pathology. |
| 2016 | Repurposing clinically approved cephalosporins for tuberculosis therapy. | Sci Rep | While modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (TB) therapy, we identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. Common chemical patterns required for activity against Mycobacterium tuberculosis were identified using structure-activity relationships (SAR) studies. Numerous cephalosporins were synergistic with rifampicin, the cornerstone drug for TB therapy, and ethambutol, a first-line anti-TB drug. Synergy was observed even under intracellular growth conditions where beta-lactams typically have limited activities. Cephalosporins and rifampicin were 4- to 64-fold more active in combination than either drug alone; however, limited synergy was observed with rifapentine or rifabutin. Clavulanate was a key synergistic partner in triple combinations. Cephalosporins (and other beta-lactams) together with clavulanate rescued the activity of rifampicin against a rifampicin resistant strain. Synergy was not due exclusively to increased rifampicin accumulation within the mycobacterial cells. Cephalosporins were also synergistic with new anti-TB drugs such as bedaquiline and Delamanid. Studies will be needed to validate their in vivo activities. However, the fact that cephalosporins are orally bioavailable with good safety profiles, together with their anti-mycobacterial activities reported here, suggest that they could be repurposed within new combinatorial TB therapies. |
| 2013 | Pipeline of drugs for related diseases: tuberculosis. | Curr Opin HIV AIDS | For the first time in decades, there are multiple new drugs in the pipeline for the treatment of tuberculosis (TB). In addition, existing drugs are being repurposed or optimized for TB with the goal of shortened treatment duration for drug-sensitive TB and safer, shorter treatments for multidrug-resistant (MDR) TB. In this review, the results of recent trials evaluating novel combination regimens for TB disease and latent TB infection are described.High-dose rifamycins (rifampin and rifapentine) and fluoroquinolones directly observed have treatment-shortening potential when used for drug-sensitive TB disease, and a 12-dose once-weekly regimen of rifapentine along with isoniazid effectively treats latent TB. Bedaquiline, an anti-TB drug with a novel mechanism of action, and Delamanid, a nitroimidazole, are entering phase 3 trials. Both improve rates of sputum culture conversion among patients with MDR-TB. Other nitroimidazoles and oxazolidinones are in Phase 2 testing, as are combinations involving multiple new chemical entities.With the resurgence of anti-TB drug discovery efforts, we now have a modestly robust pipeline of new anti-TB drugs. Several promising new regimens involving investigational and existing drugs that may be capable of shortening treatment for drug-sensitive TB and improving management of drug-resistant TB are in late-phase clinical evaluation. |