The development of resistance to existing antibiotics, coupled with a sustained decline in the success rate of the discovery of new ones, is currently leading to a point in the future where many infections could essentially be untreatable by the compounds that are available. A fundamental understanding of bacterial antibiotic tolerance and resistance mechanisms will be an important part of any future strategy aimed at solving the growing problems with treating microbial infections.
We are using a harmless, soil derived Gram-positive bacteria, Streptomyces, as a model system to investigate the mechanisms involved in sensing, responding and adapting to antibiotic attack. Streptomyces spp. produce about 70% of known antibiotics and are the ultimate source of most antibiotic resistance genes. Consequently they possess many genes involved in sensing and responding to extracellular antibiotics, and are an ideal system to use for furthering the understanding of the processes involved. Primarily, we will focus on the mechanisms underlying changes in the bacterial cell wall caused by exposure to antibiotics. The bacterial cell wall is crucial for normal cell growth, and many antibiotics that target the cell wall find use in the treatment of infectious diseases e.g. penicillin and vancomycin. Understanding the mechanisms by which bacterial cells respond to cell envelope damage is important for the future development of effective antibiotics, and for prolonging the therapeutic use of existing drugs. How damage caused externally by antibiotics inhibiting cell wall biosynthesis is communicated to the bacterial chromosome, and how the subsequent reprogramming of gene expression acts to counteract the damage is the major focus of my research.
Our research involves using functional genomics approaches including transcriptome and proteome profiling to study and characterise the response when growing cultures of bacterial cells are challenged with antibiotics. Ultimately, understanding the dynamic link between transcriptional and translational processes will extend our knowledge of the functions and systems that are important for bacterial cell wall homeostasis, and open ways by which these can be exploited in future antibiotic therapies. We also aim to progress this research into pathogens responsible for hospital acquired infections. This work has direct implications for public health, contributing to efforts to understand the molecular basis of defensive responses and resistance to antibiotics in bacteria.
Lab members: Min Jung Kwun, Wanchen Liu, Ashraf Zarkan, Kris Valdehuesa, Da-Ran Kim
1. Kwun, M.J. & Hong, H.-J. (2014) The activity of glycopeptide antibiotics against resistant bacteria correlates with their ability to induce the resistance system. Antimicrob. Agents Chemother. 58: 6303-6310.
2. Truman, A.W., Kwun, M.J., Cheng, J., Yang, S.H., Shu, J.-W., and Hong, H.-J. (2014) Antibiotic resistance mechanisms inform discovery: Identification and characterization of a novel Amycolatopsis strain producing Ristocetin. Antimicrob. Agents Chemother. 58:5687-5695.
3. Kwun, M.J., Novotna, G., Hesketh, A.R., Hill, L., & Hong, H.-J. (2013) Induction of VanS-dependent vancomycin resistance requires binding of the drug to D-Ala-D-Ala termini in the peptidoglycan cell wall. Antimicrob. Agents Chemother. 57:4470-4480.
4. Novotna, G., Vincent, K., Hill, C., Liu, C., & Hong, H.-J. (2012) A novel membrane protein, VanJ, conferring resistance to teicoplanin. Antimicrob. Agents Chemother. 56:1784-1796.
5. Hesketh, A., Hill, C., Mokhtar, J, Novotna, G., Tran, N., Bibb, M., & Hong, H.-J. (2011) Genome-wide dynamics of a bacterial response to antibiotics that target the cell envelope. BMC Genomics. 12:226.
6. Koteva, K., Hong, H.-J., Wang, X.D., Nazi, I., Hughes, D., Naldrett, M.J., Butter, M.J., & Wright, G.D. (2010) A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor. Nat Chem Biol. 6:327-329.