Regulation of toxin production by pathogenic bacteria

Many bacteria, including those that make the human body their home, are harmless. However, some bacteria interact with humans to cause disease. This often includes the production of toxic proteins that interact directly with host cells and alter their biology. Interestingly, the gene regulatory mechanisms used to control the production of toxic proteins are similar to those commonly used by benign bacteria. We are currently using knowledge acquired from well-studied gene regulatory systems to investigate the control of bacterial toxicity. Currently, we are studying two organisms in this way; Enterotoxicgenic E. coli (ETEC) and Vibrio cholerae. Both of these bacteria cause Cholera-like disease in humans. Furthermore, ETEC is a common bacterial pathogen of farmed animals.

Haycocks JR, Sharma P, Stringer AM, Wade JT, Grainger DC. (2015) The molecular basis for control of ETEC enterotoxin expression in response to environment and host. PLoS Pathog. 11(1):e1004605.

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.

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.

Wade JT, Grainger DC. (2014) Pervasive transcription: illuminating the dark matter of bacterial transcriptomes. Nat Rev Microbiol. 12:647-653.

Singh SS, Singh N, Bonocora RP, Fitzgerald DM, Wade JT, Grainger DC. (2014) Widespread suppression of intragenic transcription initiation by H-NS. Genes Dev. 28:214-219.

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.

Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. (2015) Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 13:42-51.