Combating infectious disease: probing the organization and function of toxin-antitoxin complexes as novel antibacterial drug targets
Antibiotic resistance is an urgent public health threat. The World Health Organization recently reported that ‘a post-antibiotic era - in which common infections and minor injuries can kill - far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century.’ Despite the impending crisis, only one new class of antibiotic has come to market in recent decades: a perilous gap has opened in the race for novel antibacterials and their targets. Bacterial toxin-antitoxin (TA) complexes comprise a toxin that impairs an essential cellular process and its specific antidote. TA genes are distributed widely on bacterial genomes, typically in multiple copies. Certain physiological stresses induce release of the toxin thereby triggering cell cycle arrest or death. Numerous toxins interfere with mRNA translation. Other toxins target the DNA replication machinery or perturb the cell membrane or cell wall synthesis. TAs fulfil a variety of biological roles. Certain TA modules stabilize exogenous DNA elements, including plasmids, transposons and superintegrons. TA cassettes also are implicated in bacteriophage resistance, antibiotic persistence, and biofilm formation, and additionally may function as anti-addiction modules or may act as selfish genetic elements. Intriguingly, TAs also have emerging roles in bacterial pathogenicity. Moreover, TAs have significant, although as yet largely unexplored, promise as targets for new antibacterial agents. In particular, identification of natural or synthetic molecules that stimulate toxin release may be a potent tactic to provoke bacterial cell death. This project involves probing the organization and function of TA complexes with a long-term view of developing new antibiotic strategies based on triggering release of the toxin factor from the complex. Work in the host laboratories encompasses a range of cutting-edge microbiology, molecular biological, biochemical and biophysical techniques that provide an excellent basis for a career in biosciences research.
This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.
-Saeed S, Jowitt TA, Warwicker J, Hayes F (2015) Breaking and restoring the hydrophobic core of a centromere binding protein. J. Biol. Chem. 290:9273-9283.
- Hayes F, Kedzierska B (2014) Regulating toxin-antitoxin expression: controlled detonation of intracellular molecular timebombs. Toxins 6:337-358.
- Karuppiah V, Collins RF, Thistlethwaite A, Gao Y, Derrick JP (2013) Structure and assembly of an inner membrane platform for initiation of type IV pilus biogenesis. Proc. Natl. Acad. Sci. USA 110:E4638-4647.
- Boss L, Labudda L, Wegrzyn G, Hayes F, Kedzierska B (2013) The Axe-Txe complex of Enterococcus faecium presents a multilayered mode of toxin-antitoxin gene expression regulation. PLoS ONE 8:e73569.
- Schumacher MA, Ye Q, Barge MT, Zampini M, Barillà D, Hayes F (2012) Structural mechanism of ATP induced polymerization of the partition factor ParF: implications for DNA segregation. J. Biol. Chem. 287:26146-26154.