You are here
New Approaches to Mining the Complete Actinomycete Genome to Discover Novel Beta Lactam Antibiotics
Phone: (617) 492-0913
Email: lfoulston@warpdrivebio.com
Phone: (617) 953-1916
Email: noll@warpdrivebio.com
ABSTRACT
There is a critical need to discover and develop safe and effective antibiotics for the treatment of multidrug
resistant bacterial infections Each year approximately million patients in the US get hospital acquired
infections HAIs with a mortality rate of Nearly of the bacteria causing HAIs are resistant to at least
one commonly used antibiotic Natural products NPs and their derivatives are the basis of many
pharmaceutical advances representing of FDA approved small molecule drugs over the past decades
including many important antibiotics Genome mining for novel natural products is quickly replacing traditional
approaches to antibiotic discovery However approximately of all actinomycete gene clusters are cryptic
or silent i e expressed at levels too low to detect using traditional antibacterial screening assays or not
expressed at all Warp Drive Bio WDB has sequenced over actinomycete strain genomes from
diverse sources worldwide and our proprietary genomic database contains million secondary metabolite
gene clusters Importantly of cluster families in our database have yet to be reported in the literature
This provides an unprecedented opportunity to discover structurally and mechanistically novel NPs
Our objective is to discover and develop novel lactams BLs as broad spectrum antibiotics with improved
therapeutic profiles aimed at combating current and emerging multidrug resistant Gram pathogens BLs
represent a clinically validated class widely used in antimicrobial therapy with good broad spectrum activity
and favorable safety profiles Unfortunately the emergence of multi drug resistance severely limits the clinical
efficacy of current BL antibiotics as single agents or in combination with lactamase inhibitors WDB is
deploying our proprietary natural product genome mining platform to discover novel BL antibiotics This
platform offers a new paradigm in which drug discovery is initiated at the genome level allowing rapid
identification of novel compounds that would be otherwise overlooked in a traditional activity based discovery
paradigm We first deploy our bioinformatics search engines to rapidly identify gene clusters within WDBandapos s
genomic database that encode novel BL molecules To access the potential of silent biosynthetic gene
clusters we have developed methods to systematically replace promoters inducing compound expression
Clusters are transferred into engineered heterologous expression hosts to produce novel molecules that are
isolated as extracts in a miniaturized high throughput plate format for bioassay and we utilize mass
spectrometry analytics to rapidly identify the masses of novel BLs of interest to facilitate rapid purification for
further characterization We will apply our genome mining platform to engineer express purify and
characterize the products from novel BL biosynthetic clusters in this Phase I proof of concept study Our objective is to discover and develop novel beta lactam antibiotics with improved therapeutic profiles to
combat current and emerging multidrug resistant bacteria using an innovative genomics based platform for
drug discovery
* Information listed above is at the time of submission. *