Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds against and Malaria Parasites.

SQ109 is a tuberculosis drug candidate that has high potency against and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against , , , , and , as well as against the protozoan parasites , , , , and .

Culture-Free Enumeration of in Mouse Tissues Using the Molecular Bacterial Load Assay for Preclinical Drug Development.

Background: The turnaround times for phenotypic tests used to monitor the bacterial load of , in both clinical and preclinical studies, are delayed by the organism's slow growth in culture media. The existence of differentially culturable populations of may result in an underestimate of the true number. Moreover, culture methods are susceptible to contamination resulting in loss of critical data points.

Therapy for Infection: Beyond 2018.

The current standard of care therapy for pulmonary infection is isoniazid (300 mg/day), rifampin (600 mg/day), and ethambutol (15 mg/kg/day) for 12 months after achieving sputum culture negativity. Rifampin is the key drug in this regimen. The contribution of isoniazid is unclear since its MICs against are near the peak achievable serum levels and more than 100-fold greater than the MICs for .

2-N-Arylthiazole inhibitors of Mycobacterium tuberculosis.

To develop agents for the treatment of infections caused by Mycobacterium tuberculosis, a novel phenotypic screen was undertaken that identified a series of 2-N-aryl thiazole-based inhibitors of intracellular Mycobacterium tuberculosis. Analogs were optimized to improve potency against an attenuated BSL2 H37Ra laboratory strain cultivated in human macrophage cells in vitro. The insertion of a carboxylic acid functionality resulted in compounds that retained potency and greatly improved microsomal stability.

The efflux pump inhibitor timcodar improves the potency of antimycobacterial agents.

Previous studies indicated that inhibition of efflux pumps augments tuberculosis therapy. In this study, we used timcodar (formerly VX-853) to determine if this efflux pump inhibitor could increase the potency of antituberculosis (anti-TB) drugs against Mycobacterium tuberculosis in in vitro and in vivo combination studies. When used alone, timcodar weakly inhibited M.

A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections.

New drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drug-resistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.

A Modified Bacillus Calmette-Guérin (BCG) Vaccine with Reduced Activity of Antioxidants and Glutamine Synthetase Exhibits Enhanced Protection of Mice despite Diminished in Vivo Persistence.

Early attempts to improve BCG have focused on increasing the expression of prominent antigens and adding recombinant toxins or cytokines to influence antigen presentation. One such modified BCG vaccine candidate has been withdrawn from human clinical trials due to adverse effects. BCG was derived from virulent Mycobacterium bovis and retains much of its capacity for suppressing host immune responses.

In vitro antituberculosis activities of ACH-702, a novel isothiazoloquinolone, against quinolone-susceptible and quinolone-resistant isolates.

ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of View Article and Find Full Text PDF

Short-course treatment regimen to identify potential antituberculous agents in a murine model of tuberculosis.

Objective: Designing a more rapid method to test antimycobacterial agents in a murine model would significantly improve the drug development process. We describe a short-course in vivo treatment model that could be used to screen potential antituberculous drugs.

Methods: In this model, C57BL/6 mice were infected intranasally with approximately 10(6) viable Mycobacterium tuberculosis organisms.