Discovery of benzothiazole amides as potent antimycobacterial agents.

From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12 µg/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1-2 µg/mL against Mycobacterium avium complex. The preliminary mechanism of action studies suggested these agents may target MmpL3, a mycobacterial mycolic acid transporter. The series has demonstrated in vivo efficacy in a proof of concept mouse model of M. abscessus infection.

A metabolic biosignature of early response to anti-tuberculosis treatment.

BACKGROUND: The successful treatment of tuberculosis (TB) requires long-term multidrug chemotherapy. Clinical trials to evaluate new drugs and regimens for TB treatment are protracted due to the slow clearance of Mycobacterium tuberculosis (Mtb) infection and the lack of early biomarkers to predict treatment outcome. Advancements in the field of metabolomics make it possible to identify metabolic profiles that correlate with disease states or successful chemotherapy. However, proof-of-concept of this approach has not been provided for a TB-early treatment response biosignature (TB-ETRB). METHODS: Urine samples collected at baseline and during treatment from 48 Ugandan and 39 South African HIV-seronegative adults with pulmonary TB were divided into discovery and qualification sets, normalized to creatinine concentration, and analyzed by liquid chromatography-mass spectrometry to identify small molecule molecular features (MFs) in individual patient samples. A biosignature that distinguished baseline and 1 month treatment samples was selected by pairwise t-test using data from two discovery sample sets. Hierarchical clustering and repeated measures analysis were applied to additional sample data to down select molecular features that behaved consistently between the two clinical sites and these were evaluated by logistic regression analysis. RESULTS: Analysis of discovery samples identified 45 MFs that significantly changed in abundance at one month of treatment. Down selection using an extended set of discovery samples and qualification samples confirmed 23 MFs that consistently changed in abundance between baseline and 1, 2 and 6 months of therapy, with 12 MFs achieving statistical significance (p < 0.05). Six MFs classified the baseline and 1 month samples with an error rate of 11.8%. CONCLUSIONS: These results define a urine based TB-early treatment response biosignature (TB-ETRB) applicable to different parts of Africa, and provide proof-of-concept for further evaluation of this technology in monitoring clinical responses to TB therapy.

Nontuberculous mycobacterial infection: CT scan findings, genotype, and treatment responsiveness.

STUDY OBJECTIVE: The purpose of this study was to compare the imaging findings of nontuberculous mycobacterial (NTM) infection in patients with normal and abnormal cystic fibrosis (CF) genotypes, and normal and abnormal alpha1-antitrypsin (AAT) phenotypes. DESIGN: A retrospective review of medical records and chest CT scans from 85 patients with microbiologically proven NTM infection was performed. All patients had undergone genotype analysis for CF mutations, and phenotypic evaluation for AAT status. Patients with homozygous CF or AAT were not included. Two independent observers assessed the patterns and distribution of disease, according to a standardized score sheet. In 52 patients, follow-up CT scans were obtained 1 to 46 months (mean duration, 8 months) following the initial CT scan. The CT scan findings on the follow-up scan were visually compared with those on the initial CT scan for progression or regression of abnormalities. Statistical analysis was performed to evaluate the relationship between the dominant CT scan pattern and CF/AAT status, and between CT scan pattern and radiologic change on follow-up. RESULTS: Fifteen patients (18%) were found to carry a single CF mutation, and an abnormal AAT phenotype was seen in 13 patients (15%). Three patients (3%) were found to have both a heterozygous CF mutation and a heterozygous AAT phenotype. On the initial CT scans, bronchiectasis and nodules were the most frequent findings of NTM infection in all three groups (p > 0.05). The prevalence of nodules was slightly lower in the CF group, and the prevalence of linear scarring was greater in the AAT group than in the normal group (p < 0.05). Among the 52 patients who had a follow-up CT scan, 8 (15%) had a CF mutation and 6 (12%) had an abnormal AAT phenotype. The extent and pattern of abnormality seen on the initial CT scan did not predict change on follow-up evaluation. After treatment, 40 patients (56%) with a normal CF genotype had decrease in disease extent, compared with 4 patients (25%) with a CF mutation (p < 0.05). Bronchiectasis was improved in approximately 35% of those with normal genotype, but in none of those with a CF mutation. CONCLUSION: In patients with NTM infection, the CT scan findings show only minor differences according to phenotype and genotype. Initial CT scan findings do not predict change on follow-up CT scan evaluation. However, on follow-up CT scan, patients with CF mutations are less likely to improve, while those with AAT phenotype appear to have a radiographic outcome similar to those with normal phenotype.