Invited Oral Abstract Presentation
Discovery of agricultural fungicides from natural products
Dr. Don Hahn, Quanbo Xiong, Serge Fotso, Paul Graupner, Cruz Avila Adame, George Davis, Chenglin Yao, Kevin Meyer and Carla Klittich, Dow AgroSciences, Indianapolis, IN, USA
2017 SIMB Annual Meeting and Exhibition
A key driver in the development of new antifungal agents is the desire for new modes of action (MoA) to address expanding resistance to existing fungicides, open up options for new treatment regimens and/or reduce side effects. Unfortunately, the 12 drugs approved for antifungal treatment in humans represent only four antifungal MoA. Control of fungal diseases is also important in the agricultural setting, however, unlike clinical drugs, at least 100 compounds representing over 30 MoA are used for fungicidal control in agriculture. New fungicidal MoA are essential to maintain robust tools to combat fungal diseases in the field setting. Natural products from microbes have played an important role in agriculture through the discovery of novel fungicides and new fungicidal MoA. The natural products strobilurin A and pyrrolnitrin resulted in the development of new fungicides with new MoA. Other natural products like the atpenins target existing fungicidal MoA. Through the screening of natural products and microbial extracts from a wide range of natural sources from around the globe, Dow AgroSciences has discovered a number of novel lead fungicidal chemistries. Among these lead chemistries is the novel natural fungicide the alveolides, from the fungus
Microascus alveolaris. Natural fungicides, although potent
in vitro, often lack the robust physical properties necessary for efficacy in the field setting (e.g. UV-stability, rainfastness). Using chemistry we are working to develop robust agricultural fungicides with new MoA to enhance the farmer’s toolbox for maximizing agricultural yields.
Invited Oral Abstract Presentation
Pathway-targeted approaches to decode orphan NRPS and PKS pathways
Jason Crawford, Yale University, West Haven, CT, USA
2017 SIMB Annual Meeting and Exhibition
Modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzymes represent multidomain systems responsible for the synthesis of a broad range of natural products with pharmaceutical value. The majority of these types of enzymes in expanding sequence databases are orphan, and their small molecule products remain unknown. Additionally, these enzymes can engage in “hybrid” systems to expand the structural and functional repertoire of their products. Here we discuss “pathway-targeted” and “domain-targeted” approaches to decode these orphan pathways with surgical genetic and metabolic precision. “Pathway-targeted” networking interfaces with an existing molecular networking pipeline (GNPS) and provides a visually appealing output to map relative fold-change levels, isotopic labeling information, and genetic parameters onto a targeted secondary metabolic pathway. “Domain-targeted” metabolomics combines genome editing with pathway analysis to define the general timing and functions of individual catalytic domains within these fascinating enzyme systems at the cellular metabolic level. Specifically, domain-targeted metabolomics provides a functional readout of the catalytic domain contributions to the pathway-dependent metabolome – “multidomain signatures” – which can be assigned to every node in a molecular network. These general approaches will be highlighted primarily in the context of two selected pathways, the “pepteridines” and the “colibactins.” The pepteridines are new signaling metabolites from an unprecedented type of hybrid system that links NRPS machinery and pteridine synthase machinery. The colibactins are colorectal cancer-associated NRPS-PKS hybrid metabolites, and domain-targeted metabolomics defined their heterocycle assembly steps and revealed new metabolites with potent genotoxic scaffolds.
Invited Oral Abstract Presentation
Microbes to medicine: Development of a Millennial drug discovery platform
Dr. Ashootosh Tripathi1, Sung Ryeol Park2, Ms. Pamela Schultz1, Dr. Jianfeng Wu1, Dr. Chuanwu Xi1 and David H. Sherman1, (1)University of Michigan, Ann Arbor, MI, USA, (2)Baruch S. Blumberg Institute/Natural Products Discovery Institute, Doylestown, PA, USA
2017 SIMB Annual Meeting and Exhibition
If discovery of new antibiotics continues to wane while the ability of drug resistant pathogens continues to surge, society’s medicine chest will soon lack effective treatments against a multitude of serious infections. To put the situation into context, over the last 30 years no new class of antibiotics has been introduced to mankind.
1 Moreover, the majority of pharmaceutical efforts during the past six decades have focused on the synthetic enhancement of a limited set of unique core scaffolds.
2 From these perspectives, it was envisioned that a more sustainable route to combat antibiotic resistance is the discovery of novel classes of antimicrobials, which would require a greatly improved antibiotic discovery process, and greater access to unique microbial targets. Here, I will describe a robust high throughput antibacterial discovery platform involving key resistance mechanism as target against gram-negative (
A. baumannii) pathogenic microbes. The success of the approach provided solutions for two major bottlenecks that impede the drug discovery pipeline i.e., identification of novel drug leads and overcoming resistance due to indirect microbial targeting.
3 Moreover, biosynthetic characterization of the discovered antibiotic unraveled a convergent nature of the gene cluster machinery.
4 This genetic bifurcation was then further explored to biochemically analyze and structurally characterize the substrate scope of a key gatekeeper enzyme. The study led us to isolate novel congeners through targeted precursor incorporation, resulting in production of a potent
Acinetobacter baumannii biofilm inhibitor. Further information on the analytical approach that is being applied for identification of new classes of antibiotics will be discussed.
Invited Oral Abstract Presentation
Break
2017 SIMB Annual Meeting and Exhibition
Invited Oral Abstract Presentation
Mining uncultured bacteria with comparative metagenomics and metatranscriptomics
Ian Miller1, Dr. Skylar Carlson1, Dr. Juan Lopera2, Izaak Miller1, Dr. Melany Puglisi3, Robert Kerby2, Dr. Warren Rose1, Dr. Federico Rey2 and Dr. Jason Kwan1, (1)University of Wisconsin-Madison, Madison, WI, USA, (2)University of Wisconsin - Madison, Madison, WI, USA, (3)Chicago State University, Chicago, IL, USA
2017 SIMB Annual Meeting and Exhibition
Bacteria are incredibly talented at making intricate small molecule structures, that are frequently bioactive. However, the vast majority of bacteria have never been cultured in the laboratory, representing a potentially rich vein of unexploited biosynthetic potential. Amongst bacteria that are least likely to be cultured are a group that often produce ecologically important natural products - symbionts of higher eukaryotes. Ecologically important natural products are likely to have exquisite activity against an evolved target, and if there are related therapeutic targets, such compounds could be potential drug leads. We have devised an automated method of "binning" metagenomic contigs into individual microbial genome bins, allowing the study of complex microbial communities at the resolution of single species. We will present the application of this method to determine the response of individual bacteria in a complex marine sponge microbiome to the influx of non-symbiotic species, including the upregulation of specific biosynthetic pathways. Through the correlation of upregulated biosynthetic pathways with upregulated compounds and activities, such as bacterial biofilm inhibition, we are able to discover both compounds and their biosynthetic pathways in parallel, in a microbial ecology-guided manner.
Invited Oral Abstract Presentation
Bacterial communication in situ
Alanna Condren, Katherine Zink, Chase Clark, Sofia Costa, Dr. Brian Murphy and Dr. Laura Sanchez, University of Illinois at Chicago, Chicago, IL, USA
2017 SIMB Annual Meeting and Exhibition
Microbiome studies have laid the groundwork demonstrating that bacteria are major players in host health, however the exact mechanisms by which these bacteria influence or protect hosts represents a major gap in knowledge. There are strong correlative observations from microbiome surveys that suggest microbes play essential roles in host function, but very little work has been done to uncover the chemical mechanisms underlying host-microbe interactions. We have developed orthogonal approaches to study natural products in situ. First, we have developed a matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) pipeline to rapidly profile metabolic fingerprints directly from Petri dishes. We simultaneously applied this technique to probe two model host-microbe interactions; one being a symbiotic relationship leading to colonization of epithelial cells by one specific bacterium (Vibrio fischeri and the Hawaiian bobtail squid), and the other exploring how enteric pathogens can colonize and infect a host vertebrate (V. cholerae and zebrafish). Both of these systems are native to the macroorganism and microbe, allowing us to fully characterize the underlying chemistry involved in colonization, infection, and maintenance of the relationship. We use a combination of MALDI-TOF imaging MS techniques and orthogonal molecular networking approaches to probe these two distinct systems.
Invited Oral Abstract Presentation
Screening a natural products library for HBsAg secretion inhibitors
Dr. Jason Clement1, Dr. Siddhartha Rawat1, Dennis Solaiman1, Dr. Tianlun Zhou1, Dr. Michael Goetz2, Dr. Matthew Todd2 and Sung Ryeol Park2, (1)Baruch S. Blumberg Institute, Doylestown, PA, USA, (2)Baruch S. Blumberg Institute, DOYLESTOWN, PA, USA
2017 SIMB Annual Meeting and Exhibition
The inhibition of hepatitis B virus S-antigen (HBsAg) secretion is a potentially useful target for the development of therapeutic agents for the treatment of chronic HBV infection. We have recently developed an assay for screening for HBsAg secretion inhibitors with several improved features over previous assays. Using this assay and selected follow-up assays, we have identified several extracts derived from actinomycete fermentations with HBsAg secretion inhibitory activity. We will present our results in the isolation and identification of the compounds responsible for this activity.