Research Interests:

Metabolic requirements for bacterial persistence

The ability of Mycobacterium tuberculosis (Mtb) to persist in the presence of anti-mycobacterial drugs and immune effector functions is the greatest obstacle in our attempt to eradicate tuberculosis (TB). My laboratory is investigating the hypothesis that persistence is enabled by entrance into and maintenance of a physiological state that is metabolically distinct from that of actively replicating bacilli. The aim of this work is to define this state (or series of states) and characterize pathways that are essential for its establishment and maintenance. My laboratory uses a variety of classical and novel approaches in mycobacterial genetics, biochemistry, physiology, and metabolomics to characterize i) novel aspects of intermediary metabolism in Mtb, ii) metabolic requirements for phenotypic drug tolerance, and iii) drug targets and drug-like compounds effective against persistent bacilli. While these studies address basic science questions about unique aspects of Mtb, they will also provide important contributions to the collaborative and global effort to eradicate TB.

Selected Recent Publications:

• Meehan BM, Baughn AD, Gallegos R, Malamy MH. 2012. Inactivation of a single gene enables microaerobic growth of the obligate anaerobe Bacteroides fragilis. Proc Natl Acad Sci USA. (in press)
• Besanceney-Webler C, Jiang H, Wang W, Baughn AD, Wu P. 2011. Metabolic labeling of fucosylated glycoproteins in Bacteroidales species. Bioorg Med Chem Lett. 21:4989-92.
• Vilchèze C, Baughn AD, Tufariello J, Leung LW, Kuo M, Basler CF, Alland D, Sacchettini JC, Freundlich JS, Jacobs WR Jr. 2011. Novel inhibitors of InhA efficiently kill Mycobacterium tuberculosis under aerobic and anaerobic conditions. Antimicrob Agents Chemother. 55:3889-98.
• Baughn AD, Deng J, Vilchèze C, Riestra A, Welch JT, Jacobs WR Jr, Zimhony O. 2010. Mutually exclusive genotypes for pyrazinamide and 5-chloropyrazinamide resistance reveal a potential resistance-proofing strategy. Antimicrob Agents Chemother. 54:5323-8.
• Pruksakorn P, Arai M, Kotoku N, Vilchèze C, Baughn AD, Moodley P, Jacobs WR Jr, Kobayashi M. 2010. Trichoderins, novel aminolipopeptides from a marine sponge-derived Trichoderma sp., are active against dormant mycobacteria. Bioorg Med Chem Lett. 20:3658-63.
• Baughn AD, Garforth SJ, Vilchèze C, Jacobs WR Jr. 2009. An anaerobic-type alpha-ketoglutarate ferredoxin oxidoreductase completes the oxidative tricarboxylic acid cycle of Mycobacterium tuberculosis. PLoS Pathog. 5:e1000662.
• Arai M, Sobou M, Vilchéze C, Baughn A, Hashizume H, Pruksakorn P, Ishida S, Matsumoto M, Jacobs WR Jr, Kobayashi M. 2008. Halicyclamine A, a marine spongean alkaloid as a lead for anti-tuberculosis agent. Bioorg Med Chem. 16:6732-6.
• Ojha AK, Baughn AD, Sambandan D, Hsu T, Trivelli X, Guerardel Y, Alahari A, Kremer L, Jacobs WR Jr, Hatfull GF. 2008. Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol. 69:164-74.
• Glover RT, Kriakov J, Garforth SJ, Baughn AD, Jacobs WR Jr. 2007. The two-component regulatory system senX3-regX3 regulates phosphate-dependent gene expression in Mycobacterium smegmatis. J Bacteriol. 189:5495-503.
• Baughn AD, Malamy MH. 2004. The strict anaerobe Bacteroides fragilis grows in and benefits from nanomolar concentrations of oxygen. Nature. 427:441-4.
• Baughn AD, Malamy MH. 2003. The essential role of fumarate reductase in haem-dependent growth stimulation of Bacteroides fragilis. Microbiology. 149:1551-8.
• Baughn AD, Malamy MH. 2002. A mitochondrial-like aconitase in the bacterium Bacteroides fragilis: implications for the evolution of the mitochondrial Krebs cycle. Proc Natl Acad Sci U S A. 99:4662-7.