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.

Mycobacterium talmoniae sp. nov., a slowly growing mycobacterium isolated from human respiratory samples.

A novel slowly growing, non-chromogenic species of the class Actinobacteria was isolated from a human respiratory sample in Nebraska, USA, in 2012. Analysis of the internal transcribed spacer sequence supported placement into the genus Mycobacterium with high sequence similarity to a previously undescribed strain isolated from a patient respiratory sample from Oregon, USA, held in a collection in Colorado, USA, in 2000. The two isolates were subjected to phenotypic testing and whole genome sequencing and found to be indistinguishable.

Treatment of Non-Tuberculous Mycobacterial Lung Disease.

Treatment of non-tuberculous mycobacterial lung disease (NTM-LD) is challenging for several reasons including the relative resistance of NTM to currently available drugs and the difficulty in tolerating prolonged treatment with multiple drugs. Yet-to-be-done, large, multicenter, prospective randomized studies to establish the best regimens will also be arduous because multiple NTM species are known to cause human lung disease, differences in virulence and response to treatment between different species and strains within a species will make randomization more difficult, the need to distinguish relapse from a new infection, and the difficulty in adhering to the prescribed treatment due to intolerance, toxicity, and/or drug-drug interactions, often necessitating modification of therapeutic regimens. Furthermore, the out-of-state resident status of many patients seen at the relatively few centers that care for large number of NTM-LD patients pose logistical issues in monitoring response to treatment.

Draft Genome Sequence of Mycobacterium chelonae Type Strain ATCC 35752.

Mycobacterium chelonae is a rapidly growing opportunistic nontuberculous mycobacterial (NTM) species that causes infections in humans and other hosts. Here, we report the draft genome sequence of Mycobacterium chelonae type strain ATCC 35752, consisting of 4.89 Mbp, 63.

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.

Mouse model for efficacy testing of antituberculosis agents via intrapulmonary delivery.

Here we describe an experimental murine model that allows for aerosolized antituberculosis drug efficacy testing. Intrapulmonary aerosol delivery of isoniazid, capreomycin, and amikacin to mice with pulmonary infection of Mycobacterium tuberculosis demonstrated efficacy in reducing pulmonary bacterial loads similar to that seen by standard drug delivery methods, even when lower concentrations of drugs and fewer doses were used in the aerosolized drug regimens. Interestingly, intrapulmonary delivery of isoniazid also reduced the bacterial load in the spleen.

Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection.

Azithromycin is a potent macrolide antibiotic with poorly understood antiinflammatory properties. Long-term use of azithromycin in patients with chronic inflammatory lung diseases, such as cystic fibrosis (CF), results in improved outcomes. Paradoxically, a recent study reported that azithromycin use in patients with CF is associated with increased infection with nontuberculous mycobacteria (NTM).

Torticollis in mice intravenously infected with Mycobacterium tuberculosis.

Female BALB/cAnNCrl (n = 170; age, 6 to 9 wk) mice were infected by intravenous inoculation of 5 × 10(6) cfu Mycobacterium tuberculosis strain Erdman (ATCC 35801). Between day 52 and 5 mo after infection, 10 of the 170 mice infected according to this protocol developed torticollis, including mice in treatment groups that received combination antibiotic therapy of rifampin-pyrazinamide or moxifloxacin-rifampin-pyrazinamide. Torticollis did not develop in mice receiving isoniazid- rifampin-pyrazinamide therapy, nor was it present in the cohort of aerogenically infected mice.

Preclinical testing of new drugs for tuberculosis: current challenges.

The continuing global epidemic of tuberculosis, the increasing rate of multidrug resistant (MDR) tuberculosis and the more recent emergence of extensively drug resistant (XDR) tuberculosis are great causes for concern. A major international effort is currently underway to optimize current drug therapies and to discover new drugs that are active against these organisms. This effort has created a pipeline of new candidate drugs at various stages of preclinical and early clinical evaluations.

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.

Conventional and molecular epidemiology of macrolide resistance among new Mycobacterium avium complex isolates recovered from HIV-infected patients.

We performed a retrospective cohort study of human immunodeficiency virus (HIV)-associated Mycobacterium avium complex (MAC) infection during 1997-2004 to assess for factors associated with initial macrolide resistance. Of 52 HIV-associated sterile-site MAC isolates, 9 (17%) were initially macrolide resistant. Prior MAC treatment and prolonged MAC prophylaxis with macrolides were associated with infection with a macrolide-resistant isolate; 2 (22%) of 9 patients had limited or no prior macrolide exposure.