Is it possible to identify new antibiotics by screening chemical libraries for inhibitors of cell morphogenesis and sporulation?

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 two compounds screens of a total of nearly 35,000 molecules, for molecules that block spore formation in the filamentous Streptomyces genus of bacteria.

sporulation inhibitor blocks cell cycle morphogenesis in Streptomyces venezuelae
A sporulation inhibitor blocks cell cycle morphogenesis in Streptomyces venezuelae.

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.

Various bacterial cultures.

Publications

View all Nodwell Lab research publications on PubMed

To date, the lab has conducted:

35,000

two-compounds screens for molecules that block spore formation in  Streptomyces bacteria conducted

207

chemical inhibitors of spore formation collected

The "secondary metabolome":
How it is regulated?
What purpose does it serve in nature?

Chemical Defenses from Nature

Most of our work concerns a genus of filamentous bacteria known as Streptomyces. For reasons that are currently not well understood, this genus produces a vast repertoire of biologically active small molecules, many of which have been developed as drugs.

This includes most of the antibiotics, antifungal drugs, immune suppressants and several anti-cancer drugs.

We are interested in many aspects of the ‘secondary metabolome’ including how it is regulated as well as the purpose it serves in nature.

Pink cubist strain, Nodwell Lab
Pink cubist strain.

One thing we have discovered is that many of the compounds produced by these bacteria are not expressed during laboratory culture – as a result, most of these compounds have never been investigated in molecular detail.

Bacteria produce many more compounds than those seen in laboratory culture.

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?

It is fascinating work!

Streptomyces coelicolor, the model actinomycete, produces a diffusible blue pigment with antibiotic activity called actinorhodin.
Streptomyces coelicolor, the model actinomycete, produces a diffusible blue pigment with antibiotic activity called actinorhodin.

Unusual Fungi and Deep Sea Creatures

Hyphodiscus fungi in Nodwell Lab
Hyphodiscus fungi producing a striking red colour when grown under laboratory conditions.

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.

For example, 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 have reported the genome sequence of the causative agent of the “zombie ant” phenomenon

Unusual Fungi and Deep Sea Creatures

Finally, 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 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.

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