Discovery of natural product biosynthetic gene clusters
Growing bacteria in the laboratory to harvest the bioactive molecules that they produce has historically proven a successful drug discovery strategy. It is estimated, however, that over 99% of bacteria cannot presently be grown under laboratory conditions. To overcome this limitation we extract bacterial DNA directly from biodiverse environments such as marine sponges and soil and clone it into a lab-friendly host such as Escherichia coli. We then apply functional or sequence-based screens to recover cloned DNA that includes key biosynthetic genes required for synthesis of specific classes of natural product, in particular polyketides and non-ribosomal peptides. Our ultimate goal is to express complete gene clusters in a suitable bacterial host that can be used to produce promising drug candidates affordably and in unlimited supply.
Nitroreductase enzymes for cancer gene therapy
Cancer is now the second highest cause of death in New Zealand, highlighting the need for improved treatments. One promising new approach is gene therapy, using bacteria or viruses that preferentially infect tumours to deliver a lethal genetic payload. In collaboration with researchers at the University of Auckland we have engineered genes encoding new nitroreductase enzymes that sensitise the tumours to “prodrugs” – compounds that are highly toxic when activated, but otherwise have minimal side-effects in healthy tissue. Crucially, some of our new nitroreductases can also activate positron emission tomography (PET) probes to a cell-entrapped form, opening the way for use of standard hospital PET scans to show where in a patient’s body these genes are located; and therefore whether the microbe is confined to cancerous tissue. This is a vital safety control that has been lacking in previous cancer gene therapy trials.
Enzymes for bioremediation
A number of the enzymes we have discovered are able to transform common environmental pollutants to a non-toxic form. Specific pollutants include hexavalent chromium (the pollutant at the heart of the Erin Brockovich lawsuit), dinitrotoluene explosives, and azo dyes. We have developed practical ways for producing stabilised enzymes in high yield, and for supplying them with renewable sources of (otherwise prohibitively expensive) cofactors that are required to power the detoxification reactions.
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