? This Proposal is in response to PA-01-113, """"""""Therapeutics Research on AIDS-Associated Opportunistic Infections and Malignancies"""""""" and specifically addresses the study of Mycobacterium tuberculosis (MTB). The thrust of this proposal is the development of novel drug targets to counteract multiple drug resistant organisms. The long-term goal of this research program is to develop novel classes of chemotherapeutics that target the regulation, and coordination of chromosomal segregation and cellular division in MTB. Toward this objective we have identified in the MTB genome, gene products that are homologous to proteins associated with these processes in other prokaryotes. Moreover, our preliminary results provide strong evidence that some of these gene products (FtsZ and Ftsl homologues) actively participate in the cellular division of MTB. However, a more extensive analysis of these gene products and global assessment of the potential regulatory networks involved in the division of MTB cells are required. Similar to work with Caulobacter crescentus we hypothesize that DNA microarray analysis with synchronized cultures of MTB will allow us to develop a detailed pattern of gene expression profiles across the entire cell division cycle of this bacterium. Additionally, the use of known inhibitors of early (FtsZ activity) and late (Ftsl activity) events of cell division along with global gene expression studies will further elucidate the regulatory networks that are activated during different stages of cell division. A final analysis of putative regulatory genes already identified and new ones elucidated through gene expression profiling will enable us to develop a detailed picture of the regulatory networks and temporal gene expression responsible for MTB cellular division. Such studies will ensure that future resources are well directed at appropriate chemotherapeutic targets and developing suitable drug discovery strategies. Thus, the studies proposed in this application are designed to examine the replication dynamics of MTB, specifically focusing on cell cycle-regulated genes that are involved in cell division. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Sizemore, Christine F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Colorado State University-Fort Collins
Schools of Veterinary Medicine
Fort Collins
United States
Zip Code
Crew, Rebecca; Ramirez, Melissa V; England, Kathleen et al. (2015) MadR1, a Mycobacterium tuberculosis cell cycle stress response protein that is a member of a widely conserved protein class of prokaryotic, eukaryotic and archeal origin. Tuberculosis (Edinb) 95:251-8
Ramirez, Melissa V; Dawson, Clinton C; Crew, Rebecca et al. (2013) MazF6 toxin of Mycobacterium tuberculosis demonstrates antitoxin specificity and is coupled to regulation of cell growth by a Soj-like protein. BMC Microbiol 13:240
Slayden, Richard A; Jackson, Mary; Zucker, Jeremy et al. (2013) Updating and curating metabolic pathways of TB. Tuberculosis (Edinb) 93:47-59
England, Kathleen; Crew, Rebecca; Slayden, Richard A (2011) Mycobacterium tuberculosis septum site determining protein, Ssd encoded by rv3660c, promotes filamentation and elicits an alternative metabolic and dormancy stress response. BMC Microbiol 11:79
Kumar, Kunal; Awasthi, Divya; Berger, William T et al. (2010) Discovery of anti-TB agents that target the cell-division protein FtsZ. Future Med Chem 2:1305-23
Williams, Diana L; Slayden, Richard A; Amin, Amol et al. (2009) Implications of high level pseudogene transcription in Mycobacterium leprae. BMC Genomics 10:397
Dhiman, Rakesh K; Mahapatra, Sebabrata; Slayden, Richard A et al. (2009) Menaquinone synthesis is critical for maintaining mycobacterial viability during exponential growth and recovery from non-replicating persistence. Mol Microbiol 72:85-97
Slayden, Richard A; Belisle, John T (2009) Morphological features and signature gene response elicited by inactivation of FtsI in Mycobacterium tuberculosis. J Antimicrob Chemother 63:451-7
Gonzalez-Juarrero, Mercedes; Kingry, Luke C; Ordway, Diane J et al. (2009) Immune response to Mycobacterium tuberculosis and identification of molecular markers of disease. Am J Respir Cell Mol Biol 40:398-409
Respicio, Laurel; Nair, Pravin A; Huang, Qing et al. (2008) Characterizing septum inhibition in Mycobacterium tuberculosis for novel drug discovery. Tuberculosis (Edinb) 88:420-9

Showing the most recent 10 out of 15 publications