ProfessorJeffery Errington

Project Opportunities

Title: Development of a molecular genetic platform for discovery of new bioactive natural product molecules from microbes

Summary of opportunity:

Natural product molecules made by bacteria and fungi are a hugely important source of drug starting points but it is now thought that we have hardly scratched the surface of the potential diversity in nature. The central aim of this project will be to develop new molecular genetic methods with which to open up the unexplored chemical diversity and screen the outputs for valuable new compounds.

Opportunity synopsis:

Recent genome and metagenome sequencing methods have revealed that bacteria and fungi encode a huge pool of as yet unexplored specialized metabolites (aka natural products). The majority of the coding potential lies in organisms that have not yet been cultivated or are “cryptic” and not synthesized under typical laboratory conditions. Because these molecules are genetically encoded it should be possible to use genetic and genomic methods to unlock the potential coding capacity, making them accessible to screening cascades for bioactives in the pharmaceutical and agrochemical sectors. The aim of the project will be to develop new methods with which to access novel bioactive molecules and then exploit them in bioactivity screens.

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Project Opportunities

Title: Role of cell wall deficient "L-form" bacteria in recurrent infection

Summary of opportunity:

The Errington lab has recently pioneered molecular genetic work on a remarkable bacterial physiological adaptation called the “L-form”. L-forms are variants that completely lack the highly conserved cell wall that is normally considered an essential structure. Among the unusual features of these cells is their total resistance to important antibiotics, such as penicillins, that target the cell wall. We plan to explore the likely role of L-forms in a range of recurrent infections.

Opportunity synopsis:

Cell wall deficient “L-form” bacteria were first described about 85 years ago but until recently, little was known about their distribution or abundance, nor of the molecular basis for switching in and out of the L-form state. Over the last 10 or so years the Errington lab has pioneered molecular cell biology studies of L-forms and established how they originate, how they grow and divide in the absence of a wall, and the constraints on their growth and viability. L-forms have been implicated in a wide range of recurrent infections, especially those associated with beta-lactam antibiotic use. The central aim of the project is to develop model systems for recurrent infection, and use these to directly test whether switching in and out of the L-form state can contribute to recurrence, as a prelude to clinical studies.  

----------Current Research Projects----------

The lab is currently focusing on two major areas.

1. L-form bacteria: basic properties and their possible role in recurrent infection.

2. Discovery of new natural product drug leads, and studies of NP genetics and biosynthesis

L-form bacteria

Virtually all well known bacteria possess a critically important cell wall, which is largely based on a mesh-like molecule called peptidoglycan (PG) that covers the whole cell surface. The wall is the target for our best antibiotics (penicillins, cephalosporins, etc) and is normally essential for cell viability - cells will swell and burst on most bacterial culture media if cell wall integrity is breached. However, under isotonic conditions many bacteria can switch into a state called the "L-form" in which they grow, albeit poorly, in a cell-wall-deficient state. L-forms have a wide range of interesting properties relevant to: recurrent infection, mechanisms of antibiotic killing and resistance, and even biotechnology. The lab has various ongoing projects across these areas.

Natural products

A large proportion of modern drugs are based on chemical compounds produced by living organisms, called "Natural Products" (NPs). The majority of interesting molecules are made by microbes - bacteria and fungi - and of these organisms, actinobacteria are the most prolific producers. Actinobacteria are filamentous Gram positive bacteria that live in a wide range of habitats, from deep ocean sediments to arid desert soils. Tens of thousands of NPs have been discovered in the past but recent genomics methods have revealed that we have only begun to scratch the surface of the total diversity of molecules that can be made. NPs are synthesised via complex enzyme pathways that are the source of much interest. The genes encoding the enzymes for any given NP are often grouped together in "biosynthetic gene clusters" (BGCs) that can be isolated and manipulated to control expression and generate analogue compounds by rational design. The lab is working on novel methods to isolate new NPs, to isolate, characterise and manipulate BGCs, and to discover and develop new molecules with therapeutic potential.