Opportunities and Challenges in Activity-Based Protein Profiling of Mycobacteria
Mycobacteria, from saprophytic to pathogenic species, encounter diverse environments that demand metabolic versatility and rapid adaptation from these bacteria for their survival. The human pathogen Mycobacterium tuberculosis, for example, can enter a reversible state of dormancy in which it is metabolically active, but does not increase in number, and which is believed to enable its survival in the human host for years, with attendant risk for reactivation to active tuberculosis. Driven by the need to combat mycobacterial diseases like tuberculosis, efforts to understand such adaptations have benefitted in recent years from application of activity-based probes. These studies have been inspired by the potential of these chemical tools to uncover protein function for previously unannotated proteins, track shifts in protein activity as a function of environment, and provide a streamlined method for screening and developing inhibitors. Here we seek to contextualize progress thus far with achieving these goals and highlight the unique challenges and opportunities for activity-based probes to further our understanding of protein function and regulation, bacterial physiology, and antibiotic development.
We thank Dr. Benjamin Cravatt, Dr. Peter Tonge, and members of the Seeliger laboratory for helpful discussions on topics and concepts discussed in this review.
- Cravatt BF, Wright AT, Kozarich JW (2008) Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu Rev Biochem 77:383–414. https://doi.org/10.1146/annurev.biochem.75.101304.124125CrossRefGoogle Scholar
- Duckworth BP, Wilson DJ, Nelson KM, Boshoff HI, Barry CE 3rd, Aldrich CC (2012) Development of a selective activity-based probe for adenylating enzymes: profiling MbtA Involved in siderophore biosynthesis from Mycobacterium tuberculosis. ACS Chem Biol 7:1653–1658. https://doi.org/10.1021/cb300112xCrossRefPubMedPubMedCentralGoogle Scholar
- Gold B, Nathan C (2017) Targeting phenotypically tolerant Mycobacterium tuberculosis. Microbiol Spectr 5 https://doi.org/10.1128/microbiolspec.tbtb2-0031-2016
- Portevin D, De Sousa-D’Auria C, Houssin C, Grimaldi C, Chami M, Daffe M, Guilhot C (2004) A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in mycobacteria and related organisms. Proc Natl Acad Sci U S A 101:314–319. https://doi.org/10.1073/pnas.0305439101CrossRefPubMedGoogle Scholar
- Ravindran MS, Rao SP, Cheng X, Shukla A, Cazenave-Gassiot A, Yao SQ, Wenk MR (2014) Targeting lipid esterases in mycobacteria grown under different physiological conditions using activity-based profiling with Tetrahydrolipstatin (THL). Mol Cell Proteomics 13:435–448 https://doi.org/10.1074/mcp.m113.029942CrossRefGoogle Scholar
- Touchette MH, Holsclaw CM, Previti ML, Solomon VC, Leary JA, Bertozzi CR, Seeliger JC (2015) The rv1184c locus encodes Chp2, an acyltransferase in Mycobacterium tuberculosis polyacyltrehalose lipid biosynthesis. J Bacteriol 197:201–210. https://doi.org/10.1128/JB.02015-14CrossRefPubMedGoogle Scholar
- Viader A et al. (2016) A chemical proteomic atlas of brain serine hydrolases identifies cell type- specific pathways regulating neuroinflammation Elife 5 https://doi.org/10.7554/elife.12345