Gene regulation in pathogenic bacteria
Many bacteria, including those that make the human body their home, are harmless. However, some bacteria interact with humans and other animals to cause disease. This often includes the production of toxic proteins that interact directly with host cells and alter their biology. The gene regulatory mechanisms used to control the production of such toxins, and other proteins important for the bacterium to colonise the host, are of great interest. We are currently trying to understand how pathogenic bacteria regulate genes to manage host colonisation and cause disease. Most of our work in this area is focussed on Vibrio cholerae, the causative agent of the pandemic disease cholera. We also have interests in enterotoxigenic E. coli (ETEC), Salmonella and Acinetobacter baumannii.
Haycocks JRJ, Warren GZL, Walker LM, Chlebek JL, Dalia TN, Dalia AB, Grainger DC (2019). The quorum sensing transcription factor AphA directly regulates natural competence in Vibrio cholerae.
PLoS Genet. 15:e1008362.
Guest T, Haycocks JRJ, Warren GZL, Grainger DC (2022) Genome-wide mapping of Vibrio cholerae VpsT binding identifies a mechanism for c-di-GMP homeostasis. Nucleic Acids Res. 50:149-159.
Controlling genes on a chromosome-wide scale
The control of bacterial gene expression, particularly the control of transcription, has been studied since the dawn of molecular biology. Early studies established fundamental models of transcriptional control that still hold true today. However, recent work has revealed unprecedented complexity in transcriptional regulatory systems. These complexities are best understood using a combination of chromosome-wide and focused molecular techniques. A current research goal is to understand the intricate nature of transcription and its control at genes that have an unusual abundance of A and T nucleotides. Our work to date has shown that such genes have a tendency to fire undesirable transcriptional events that may impinge on aspects of biology as diverse as metabolism and evolution.
Forrest D, Warman EA, Erkelens AM, Dame RT, Grainger DC (2022) Xenogeneic silencing strategies in bacteria are dictated by RNA polymerase promiscuity. Nat Commun. 13:1149.
Warman EA, Forrest D, Guest T, Haycocks JJRJ, Wade JT, Grainger DC (2021) Widespread divergent transcription from bacterial and archaeal promoters is a consequence of DNA-sequence symmetry.
Nat Microbiol. 6:746-756.
Lamberte LE, Baniulyte G, Singh SS, Stringer AM, Bonocora RP, Stracy M, Kapanidis AN, Wade JT, Grainger DC. (2017) Horizontally acquired AT-rich genes in Escherichia coli cause toxicity by sequestering RNA polymerase. Nat Microbiol. 2:16249.
Understanding Multiple Antibiotic Resistance in Gram Negative Bacteria
Many bacteria are now resistant to some, or all, antibiotics. The multiple antibiotic resistance (mar) system, or its paralogs (e.g. ram and sox) in other species, play a key role in facilitating drug resistance. Consequently, mar has become a focus of our work. Briefly, the mar system encodes two transcription factors; a repressor called MarR and an activator called MarA. Usually, MarR prevents MarA expression. However, in multidrug resistant bacteria, the marR gene and integenic region often contain mutations, which render MarR poorly active. Consequently, MarA is over-expressed. Once expressed, MarA switches on bacterial defence systems that protect cells against many antimicrobial compounds. Surprisingly, most genes targeted by MarA have not been defined. This is a significant omission; MarA targets will include hitherto undescribed determinants for antibiotic resistance and potential novel therapeutic targets. Our aim is to identify all genes controlled by MarA, or its paralogs, and define the underlying mechanisms of antibiotic resistance. We expect the resistance mechanisms to be broadly conserved in Gram-negative bacteria.
Kettles RA, Tschowri N, Lyons KJ, Sharma P, Hengge R, Webber MA, Grainger DC (2019) The Escherichia coli MarA protein regulates the ycgZ-ymgABC operon to inhibit biofilm formation. Mol Microbiol. 112:1609-1625.
Sharma P, Haycocks JRJ, Middlemiss AD, Kettles RA, Sellars LE, Ricci V, Piddock LJV, Grainger DC (2017) The multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity. Nat Commun. 8:1444.