Driving the Way to Tuberculosis Elimination: The Essential Role of Fundamental Research.

Tuberculosis has impacted human health for millennia. The World Health Organization estimated that, in 2014, 9.6 million people developed tuberculosis and 1.5 million people died from the disease. In May 2014, the World Health Assembly endorsed the new "End TB Strategy" that presents a pathway to tuberculosis elimination. The strategy outlines 3 areas of emphasis, one of which is intensified research and innovation. In this article we highlight the essential role for fundamental tuberculosis research in the future of tuberculosis diagnostics, treatment, and prevention. To maximize the impact of fundamental research, we must foster collaboration among all stakeholders engaged in tuberculosis research and control to facilitate open dialogue to assure that critical gaps in outcome-oriented science are identified and addressed. We present here a framework for future discussions among scientists, physicians, research and development specialists, and public health managers for the reinforcement of national and international strategies toward tuberculosis elimination.

An array of target-specific screening strains for antibacterial discovery.

As the global threat of drug- and antibiotic-resistant bacteria continues to rise, new strategies are required to advance the drug discovery process. This work describes the construction of an array of Escherichia coli strains for use in whole-cell screens to identify new antimicrobial compounds. We used the recombination systems from bacteriophages lambda and P1 to engineer each strain in the array for low-level expression of a single, essential gene product, thus making each strain hypersusceptible to specific inhibitors of that gene target. Screening of nine strains from the array in parallel against a large chemical library permitted identification of new inhibitors of bacterial growth. As an example of the target specificity of the approach, compounds identified in the whole-cell screen for MurA inhibitors were also found to block the biochemical function of the target when tested in vitro.

The role of biomedical research in global tuberculosis control: gaps and challenges: A perspective from the US National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Tuberculosis (TB) has been a persistent public health concern for hundreds of years. Despite advances in medicine and science, eliminating this disease has been beyond our reach. Several organizations, including the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have expressed their commitment to advancing biomedical research in TB in order to increase our understanding of the causative pathogen and the disease. This basic knowledge is a critical first step in the development and implementation of new therapeutics, vaccines and diagnostics. Collaboration between researchers is a key component to accomplishing this goal; product development can no longer be limited to separate programs. Rather, the interconnectedness and possible combination of interventions must be investigated. This review will discuss ongoing TB research including NIAID's role, as well as future research that is needed to improve TB control. Emphasizing the importance of coordination among researchers, funders and advocacy groups, we aim to illustrate the fact that biomedical research, and particularly basic research, is a vital part of a complementary approach to eliminating TB across the globe.

Tuberculosis vaccine development: research, regulatory and clinical strategies.

In the past decade, while the global tuberculosis (TB) epidemic has continued to devastate mankind, considerable progress has nevertheless been made in the development of new and improved vaccines for this ancient disease. Recombinant bacillus Calmette-Guerin strains, DNA-based vaccines, live attenuated Mycobacterium tuberculosis vaccines and subunit vaccines formulated with novel adjuvants have shown promise in preclinical animal challenge models. Three of these vaccines are being evaluated at present in human clinical studies, and several other vaccine preparations are being targeted for clinical trials in the near future. Although the preclinical characterisation and testing of new TB vaccines has clearly led to exciting new findings, complex regulatory and clinical trial design issues remain as a challenge to TB vaccine development. This report reviews some of the exciting advances in TB research that have led to the development of new TB vaccines, and addresses the unique regulatory and clinical issues associated with the testing of novel anti-TB preparations in human populations.

Effects of metronidazole, tetracycline, and bismuth-metronidazole-tetracycline triple therapy in the Helicobacter pylori SS1 mouse model after 1 day of dosing: development of an H. pylori lead selection model.

We evaluated the effect of optimized doses and dosing schedules of metronidazole, tetracycline, and bismuth-metronidazole-tetracycline (BMT) triple therapy with only 1 day of dosing on Helicobacter pylori SS1 titers in a mouse model. A reduction of bacterial titers was observable with 22.5 and 112.5 mg of metronidazole per kg of body weight (as well as BMT) given twice daily and four times daily (QID). Two hundred milligrams of tetracycline per kilogram, given QID, resulted in only a slight reduction of H. pylori titers in the stomach. We argue that optimization of doses based on antimicrobial drug levels in the animal and shortened (1 or 2 days) drug administration can be used to facilitate early evaluation of putative anti-H. pylori drug candidates in lieu of using human doses and extended schedules (7 to 14 days), as can be deduced from the results seen with these antimicrobial agents.