Around two thirds of previous antimicrobial compounds are derived from so called bacterial Natural Products which typically have potent specific activities. Importantly, all natural products serve specific biological roles unlike the majority of molecules in synthetic compound libraries. If we can determine their activities we may exploit them for unmet medical needs. Many natural products produced by bacteria are used to combat their competitors and predators, thus presenting a useful source of potential novel antimicrobial drug candidates. Free-living saprophytic soil bacteria such as the Streptomyces have proved a fruitful hunting ground for natural products in the past. However in order to combat the rising threat of antimicrobial resistance, we need to develop novel antimicrobials that exhibit new modes of action distinct from those of current drug targets.

We suggest that the best chance of finding these is to diversify the range of bacteria in which we are searching to those with more unconventional and varied life cycles. Bioinformatic analysis of the ever-increasing number of bacterial genome sequences has revealed the huge cache of secondary metabolism genes (for natural product synthesis) in diverse bacteria that could in theory be exploited to identify new drugs.

We are currently developing an imaginative trans-disciplinary methodological pipeline that will grant access to this wealth of cryptic natural products inferred from genome sequences. We focus on the insect and human pathogenic genus Photorhabdus. These bacteria are sufficiently closely related to E. coli that many available genetic tools are applicable, and importantly this also readily allows for heterologous expression.

Of key significance is that the Photorhabdus life cycle demands that they produce a range of potent antimicrobial compounds. They are vectored into insect larvae in the soil by a symbiont nematode, whereupon they rapidly kill the insect. Astonishingly, these bacteria are then able to keep the cadaver free from invading prokaryote and eukaryotic microbes for up to one month by deploying a cocktail of antimicrobial molecules. We previously concluded a 7^th framework EU collaborative programme (GAMEXP) in which we successfully isolated and determined the structure of many novel natural products from Photorhabdus and Xenorhabdus . Some of these have very valuable actives such as the selective killing of the Malaria parasite Plasmodium and antibiotic activity against resistant bacteria such as MRSA. Despite this, our comparative genomics and RNA-seq studies have indicated that over 50% of the NP synthetic genes of any given strain are not expressed under laboratory conditions. Our methodological pipeline will circumvent this bottleneck and allow us to begin to systematically produce and screen these cryptic natural products for exploitation as future antimicrobial drugs. Genomic studies showed us that each strain encodes between 20-30 gene clusters for natural product production. Furthermore less than half of these are common to all strains, with the remainder being very diverse and dependent upon the geographic source of strain isolation. This one genus alone therefore offers an unparalleled resource and exploitable opportunity for many years to come.

Nick Waterfield is a member of Warwick Antimicrobial Interdisciplinary Centre (WAMIC) leadership team.

http://www2.warwick.ac.uk/fac/cross_fac/wamic/people

WAMIC aims to bring together researchers from diverse disciplines in order to combat the threat of antimicrobial resistance. Drug-resistant infections could kill an extra 10 million people across the world every year by 2050 if they are not tackled. By this date they could also cost the world around $100 trillion in lost output. In addition, Waterfield is also a member of the cross-department management team for a recent EPSRC "bridging the gaps" award made to Prof. Matt Keeling (School of Life Sciences & Mathematics Institute) which will boost efforts into tackling antimicrobial resistance.

Waterfield is also a member of the "Npronet" online community dedicated to fostering collaboration and development in Natural Product research;

http://npronet.com/