Project Summary:

New drugs to treat TB are urgently needed. Unfortunately, few new drugs and drug targets have been validated against Mycobacetrium tuberculosis (Mtb) despite considerable advances in our understanding of the biochemistry and metabolism of this bacetrium. It has become apparent that not all essential metabolic processes represent good drug targets in bacetria. Fortunately, years of drug development efforts have revealed a number of bacetrial processes that do appear to contain good targets for antibacetrials. These processes include cell wall biosynthesis, protein synthesis and DNA gyrase. In the case of Mtb, respiration also appears to be a promising druggable cellular process. We propose to discover and develop inhibitors that target these druggable processes. To this end, we have developed a screen that broadly detects cell wall biosynthesis inhibitors. We have also demonstrated that our screen efficiently identifies promising drug leads that are active against Mtb and are specific to this process. Our group has already characetrized the activity and identified the novel target of a class of compounds (theophenes or TPs) that were first identified in our cell wall biosynthesis inhibitor screen. The TPs inhibit Pks13, an essential enzyme involved in mycolic acid biosynthesis. These compounds have cidal activity against Mtb and eliminate persisters in vitro when used in combination with the first line anti-TB drug isoniazid. Our screening/discovery approach can also be adapted to identify inhibitors that are specific to other druggable cellular processes. Here, we propose to develop the most promising cell wall inhibitors that we have discovered into optimized drug leads. We will also fully characetrize the remaining hits from our screen. We will also expand our screening approach to uncover new inhibitors and novel targets in the druggable processes of protein synthesis, DNA gyrase and respiration. Our three specific aims are to: 1) Optimize the drug properties of our lead TP compounds. 2) Discover the targets of novel cell wall inhibitors identified by our cell wall screen, and study the metabolic consequences of target inhibition. 3) Identify new hit compounds that inhibit targets within pathways essential to protein synthesis, DNA gyrase, and respiration.


Dr. Alland received a BA in Psychology from Columbia College at Columbia University and an MD from The Columbia College of Physicians and Surgeons.  He completed a Residency in Internal Medicine at Columbia Presbyterian Hospital (now The New York-Presbyterian Hospital) and then spent a year in London studying Tropical Medicine at the London School of Hygiene and Tropical Medicine where he received an MSc. in Clinical Tropical Medicine and a DTM&H.  Dr. Alland performed a clinical fellowship in Infectious Disease at Montefiore Medical Center and then a research fellowship in the laboratory of Barry Bloom at the Albert Einstein College of Medicine.  He stayed on at Albert Einstein/Montefiore as faculty and then moved to New Jersey Medical School – UMDNJ where he soon became Professor and Chief of the Division of Infectious Disease.  He is currently also the Director of the Center for Emerging Pathogens and the Associate Dean for Clinical Research at New Jersey Medical School. Dr. Alland’s laboratory studies various aspects of drug tolerance and drug resistance in Mycobacetrium tuberculosis with an emphasis on drug resistance evolution, resistance and tolerance mechanisms, and molecular diagnostics.  His laboratory also studies tuberculosis phylogenetics and pathogenesis and has an active program in bacetrial sepsis diagnostics.  Dr. Alland developed the Xpert MTB/RIF assay, the first commercial assay that can detect the presence of M. tuberculosis and resistance to the drug rifampin directly from a clinical sputum sample in collaboration with Cepheid.  His laboratory continues to work on M. tuberculosis molecular diagnostics including advanced applications of the Xpert assay.  Dr. Alland has received numerous NIH grant awards and he currently serves as a member of the NIH CRFS study section and the ACTG Tuberculosis Transformational Science Committee.

Contact info:

David Alland, MD
Professor and Chief, Division of Infectious Diseases
Director, Center for Emerging Pathogens
Associate Dean for Clinical Research
Rutgers-New Jersey Medical School
185 South Orange Avenue
Newark, NJ 07103
Office: 973 972 2179
Fax: 973 972 0713