Our group works on many different antibiotic-producing and pathogenic microorganisms! Check out our projects below!
Chemical defences from nature
Bacteria produce so many more compounds than we have seen in laboratory conditions!
One area of focus involves the genus of filamentous bacteria known as Streptomyces. For reasons not well understood, this genus produces a vast repertoire of biologically active small molecules – many of which have been developed into drugs.
Known as the ‘secondary metabolome‘, we are extremely interested in how it is regulated and the purpose each molecule serves in nature!
Many compounds produced by these bacteria are not expressed in laboratory cultures – as a result, most of these compounds have never been investigated in molecular detail!
We have developed a number of genetic and chemical properties for inducing these pathways and now use them to identify and purify these ‘cryptic’ compounds.
We use a variety of technologies to understand their molecular action – much of this work is intended to understand their target organism: we find that these include everything from bacteriophages to higher eukaryotes.
Once we identify a compound of interest we seek to understand its action in biochemical and genetic detail: what is its molecular target and what are the consequences of the molecule/target interaction?
Cell shape and cell fate
Is it possible to identify new antibiotics by screening chemical libraries for inhibitors of cell morphogenesis and sporulation? This is a question we started pursuing some years ago and our results are very encouraging. We have conducted 2 compounds screens of a total of nearly 35,000 molecules, for molecules that block spore formation in the filamentous Streptomyces genus of bacteria.
The filamentous nature of Streptomyces cells means that they deploy fundamental mechanisms like cell division and chromosome segregation differently than “conventional” rod shaped and coccoid bacteria. We reasoned, therefore, that sporulation inhibitors might impinge on these mechanisms in new and potentially important ways.
To date we have collected 207 chemical inhibitors of spore formation. The most interesting outcome from this work is that many of these molecules area also active against rod shaped bacteria like Bacillus subtilis and coccoid pathogens like Staphylococcus aureus.
The phenotypic effects of these molecules are remarkable and include mechanisms involved in cell division, the regulation of cell size and chromosome stability. Most importantly, many of them have antibacterial properties as well suggesting that these molecules could serve as foundations for developing therapeutics against antibiotic resistant pathogens.
Unusual fungi and deep sea creatures
The sources of biologically active molecules in nature appear to be limitless but even against this staggeringly large backdrop, most research is focused on a narrow spectrum of organisms. For this reason, we are also involved in projects aimed at tapping new biological niches and unknown organisms to identify the full spectrum of biologically active molecules in nature.
Currently, we have a growing collection of marine bacteria. We harvest these as free-living microbes from marine sediments and seawater. In addition, we have initiated work aimed at mapping the microbiomes of deep-see molluscs. The aim of this work is to identify new species of bacteria, sequence their genomes and identify the biologically active molecules that they produce.
We are studying a bizarre genus of fungal insect pathogen referred to as Cordyceps. These fascinating organisms are incredibly diverse and include the causative agent of the “zombie ant” phenomenon (hijacking of ants for survival and reproduction!) as well as the source of many traditional medicines harvested in various Asian countries.
We have recently reported the first full-length genome sequence of a Cordyceps and we are now conducting experiments aimed at understanding the biologically active molecules encoded in this chromosome.
Identifying weaknesses in superbugs
Staphylococcus aureus is a ubiquitous opportunistic pathogen that is widely known from its infamous superbug form, MRSA (methicillin-resistant S. aureus). MRSA preys on the immunocompromised, resulting in persistent infections that evade most treatments, namely last line antibiotics such as vancomycin. In some cases, treatment with vancomycin selects for further, genetically-diverse, drug resistant forms.
Our lab has identified an Achilles’ heel in these superbugs. Resistance to cell wall-targeting antibiotics comes at the cost of hypersensitivity to a drug called tunicamycin. By uncovering the underlying mechanism of this sensitivity, this work has highlighted a novel description of the interconnected pathways regulating peptidoglycan synthesis, degradation, and recycling.
Ongoing studies on this project seek to understand the regulation of peptidoglycan recycling, feedback between recycling and degradation, and other possible molecular pathways underlying tunicamycin hypersensitivity.
changes – most notably, antibiotic resistance.
September 2023