Throughout history, infectious diseases were a leading cause of human death. In the 20th century, social improvements, antimicrobial chemotherapy and immunization led to a brief period in which infectious diseases were viewed as torments of the past. However, the emergence of new infectious agents and the reemergence of old diseases demonstrated that continued awareness, research and development are necessary to limit the impact of infectious diseases on human health. Tuberculosis (TB) remains the second leading cause of human death from an infectious disease. Drug resistant strains of Mycobacterium tuberculosis (Mtb) threaten the success of TB control programs worldwide and new drugs are needed to effectively treat patients suffering from drug resistant TB and to prevent the spread of drug resistant TB. Genes Mtb requires for growth in vitro and during infections are among the most attractive targets for the development of new drugs. However, approximately a third of Mtb's in vitro essential genes remain of unknown function, which severely limits their value for drug development. The long term goal of this application is to overcome this limitation for drug development and to increase our understanding of the biological processes that are fundamental to the growth and survival of Mtb. To achieve this we will utilize conditional gene silencing approaches to construct conditional Mtb knockdown mutants that allow the partial inactivation of In vitro essential genes. We will then (i) perform extensive phenotypic characterization to better understand when and why a gene is required for growth and when and if its inactivation is lethal to the pathogen, and (ii) apply a variety of functional genomics approaches to mechanistically characterize gene functions.

Public Health Relevance

Tuberculosis (TB) is the world's second leading cause of premature human death from an infectious disease. Work outlined in this proposal will directly increase our understanding of essential Mycobacterium tuberculosis gene functions, contribute to the development of new TB drugs, and ultimately help reducing the impact of this disease on global health.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Harvard University
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Lovewell, Rustin R; Sassetti, Christopher M; VanderVen, Brian C (2016) Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection. Curr Opin Microbiol 29:30-6
Cheng, Yu-Shan; Sacchettini, James C (2016) Structural Insights into Mycobacterium tuberculosis Rv2671 Protein as a Dihydrofolate Reductase Functional Analogue Contributing to para-Aminosalicylic Acid Resistance. Biochemistry 55:1107-19
Boutte, Cara C; Baer, Christina E; Papavinasasundaram, Kadamba et al. (2016) A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis. Elife 5:
Baric, Ralph S; Crosson, Sean; Damania, Blossom et al. (2016) Next-Generation High-Throughput Functional Annotation of Microbial Genomes. MBio 7:
Olive, Andrew J; Sassetti, Christopher M (2016) Metabolic crosstalk between host and pathogen: sensing, adapting and competing. Nat Rev Microbiol 14:221-34
DeJesus, Michael A; Ioerger, Thomas R (2015) Capturing Uncertainty by Modeling Local Transposon Insertion Frequencies Improves Discrimination of Essential Genes. IEEE/ACM Trans Comput Biol Bioinform 12:92-102
Shell, Scarlet S; Wang, Jing; Lapierre, Pascal et al. (2015) Leaderless Transcripts and Small Proteins Are Common Features of the Mycobacterial Translational Landscape. PLoS Genet 11:e1005641
Long, Jarukit E; DeJesus, Michael; Ward, Doyle et al. (2015) Identifying essential genes in Mycobacterium tuberculosis by global phenotypic profiling. Methods Mol Biol 1279:79-95
Murphy, Kenan C; Papavinasasundaram, Kadamba; Sassetti, Christopher M (2015) Mycobacterial recombineering. Methods Mol Biol 1285:177-99
Baer, Christina E; Rubin, Eric J; Sassetti, Christopher M (2015) New insights into TB physiology suggest untapped therapeutic opportunities. Immunol Rev 264:327-43

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