update on antimicrobial research
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Update on Antimicrobial Research. Prepared for Florida Citrus Industry Annual Conference Bonita Springs, FL June 12, 2014. Requirements for Management. Slow spread of disease – CHMA and insect control Treat existing infected trees Protect new plantings - PowerPoint PPT PresentationTRANSCRIPT
Update on Antimicrobial Research
Prepared for Florida Citrus Industry Annual ConferenceBonita Springs, FLJune 12, 2014
Requirements for Management• Slow spread of disease – CHMA and insect
control • Treat existing infected trees• Protect new plantings• Provide long-term sustainable genetic and
biological solutions
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Requirements for Management• ✔ Slow spread of disease – CHMA and
psyllid control – Stewardship of existing products– Label expansions– Bee health - coordination– New insect control actives
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Requirements for Management• Treat existing infected trees
– Enhanced nutritionals – Plant growth regulators– Naturally occurring microbes– Thermal therapy– Antibacterial compounds
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Outline• Perspective – science, business, regulatory,
market aspects of current challenge• Definitions – different languages• Resources available today• What have we learned?• Pipeline of bactericides• From where will the next products come?
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Some Definitions• Antibacterial treatments• Bactericides and Pesticides
– Biopesticides (Microbial and Biochemical)– Antibiotics
• Use pattern, residues, tolerance or exemption• Science
– evidence over opinions, assumptions explicit, bounds what is known as well as what is unknown, creates technology options
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Time to Market - Present Investment
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3 YR 6 YR 9 YR
Vector Pathogen Host
Time
Pro
babi
lity
Bactericides for Crops• To our knowledge in all of US there are only
three bactericides approved for use on food crops (excluding copper); Oxytetracycline, Streptomycin and Kasugamycin
• This problem is much bigger than citrus but it is ours to solve
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Registration of a New Active• A partial list of studies required by EPA
(Additional agencies may include USDA-APHIS, FDA, CDC)–(GLN 835.1240) Soil Column Leaching and (GLN 835.2410) Photodegradation of Parent and Degradates in Soil, (GLN 835.6100) Terrestrial Field Dissipation–(GLN 835.4200) Anaerobic Soil Metabolism, (GLN 835.4100) Aerobic Soil Metabolism, (GLN 835.4300) Aerobic Aquatic Metabolism and (GLN 835.4400) Anaerobic Aquatic Metabolism–(GLN 835.2120) Hydrolysis of Parent and Degradates as a Function of pH at 25° C and (GLN 835.2240) Direct Photolysis Rate of Parent and Degradates in Water
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Registration of a New Active• Some more EPA data requirements
– (GLN 850.1025) Oyster Acute Toxicity, (GLN 850.1035) Mysid Acute Toxicity, (GLN 850.1075) Saltwater Fish Acute Toxicity, (GLN 850.1075) Freshwater Fish Acute Toxicity,(GLN 850.1300) Freshwater Invertebrate Life Cycle, (GLN 850.2300) Avian Reproduction, (GLN 850.1010) Freshwater Invertebrates Acute Toxicity
– (GLN 850.4100) Terrestrial Plant Toxicity – Tier 1 Seedling Emergence, (GLN 850.4150) Terrestrial Plant Toxicity – Tier 1 Vegetative Vigor, (GLN 850.4400) Aquatic Plant Toxicity – Tier 1 Vascular, (GLN 850.5400) Aquatic Plant Toxicity – Tier 1 Nonvascular
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Registration of a New Active• Further animal EPA data requirements
– (GLN 850.2100) Avian Oral Toxicity, (GLN 850.2200) Avian Dietary Toxicity
– (GLN 850.3020) Honeybee Acute Contact Toxicity
• Human health– (GLN 870.7800) Immunotoxicity– Resistance studies with human pathogens planned for
frequency of resistance determination
• Other studies as directed…
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SEARCH FOR AGRICULUTRAL THERAPEUTICS
Citrus Greening Disease (Huonglongbing)
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Biological Assays• Graft-based assay
– Infected scion soaked in test solution and grafted onto uninfected rootstock, follow by PCR
– Slow, low-throughput – Evidence of efficacy in planta and first look at
phyto-toxicity– Open contest with InnoCentive™ promotion
• Liberibacter crescens culture-based assay– Much faster, higher-throughput followed by in
planta confirmation on CLas04/21/23 www.citrusrdf.org 14
Prior Results• Compounds screened
– ~100+ by graft graft assay and – ~400+ by culture assay
• Wide variety of categories of chemicals– Antibiotics and agricultural antibiotics– Polycation polymers– Biopesticides, plant essential oils, terpenoids– New actives and non-antibiotic derivatives– Host immune modulators
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What are we looking for?• HLB treatment; effects on tree symptoms
through CLas titre reduction • Sources: Solutions Page, Research, Companies• Chemical properties
– MW: < 450 g/mol preferably < 250 g/mol– Log Kow: 2 to 4– pKa: 2 to 6.5 preferably 3 to 5.5
• Volume of phloem: 10 ft tree, 1000 L• ? pH: 8.0 – 6.0 stylectomy vs fractionation04/21/23 www.citrusrdf.org 16
Relationships• Looking inside the box…
– Companies, facilitate turn-key screening
• Looking outside the box…– Repurpose products with regulatory advantage– Failed antibiotics with good safety profiles– 25(b) minimal risk pesticides– All commercial compounds fitting our chemical
profile and having existing tolerances on other food crops
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Current Testing Resources
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Requirements and Results
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Risk Remaining at this Stage• Technical
– Commercial scale delivery, efficacy, phytotoxicity
• Cost• Regulatory• Commercial Partner(s) • Market acceptance
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Build on Success–Expanding Teams• Pivot our focus – connecting corporations• Sponsored research base from CRDF and
others, researchers, reviewers, public solutions• Improved communication; knowledge and data
sharing between and within grower, researcher, government, corporate sectors
• CRDF Board and Committees; RMC, CPDC, IRCC• Research pipeline now enhanced with
government funding $21mm MAC, $25mm SCRI 04/21/23 www.citrusrdf.org 22
What comes next?
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Category of Compounds Description Partner
Antibiotics OxytetracyclineStreptomycin (Kasugamycin?)
Commercial
GRAS-like Plant Essential OilsNatural Products– cymene, carvacrol, etc.
CRDF-sponsored formulation research
Category of Compounds Description Partner
Agricultural Antibiotics ZhongshengmycinValidoxylamine A
Source? - Research
1. Field trials with top priority
2. Field trials with major challenges
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Category of Compounds Description Partner
Biopesticides Surfactin (lipopetides) Company C
Host Immune Modifiers One marketed compoundOne pipeline compound
Company C
3. Field trials with commercial partners
4. Development pipeline
Category of Compounds Description Partner
Polycation polymers Proprietary biodegradable polymers Company D
Bacterial protein targetLdtR
(Gonzalez)
Lead refinement-Highly active, no human homolog, transcription regulator, essential role in cell wall remodeling
Company D
Bacterial protein target SecA
(Wang)
Lead refinement-Highly active, no human homolog, protein secretion, essential role in effector secretion
Company D
Non-antibiotic derivatives Tetracycline derivatives Company E
Acknowledgements:Bob Shatters, USDA-Ft. Pierce, FLEd Stover, USDA-Ft. Pierce, FLChuck Powell, UF-Ft. Pierce, FLPing Duan, USDA-Ft. Pierce, FLMuqing Zhang, UF-Ft. Pierce, FLEric Triplett, UF-Gainesville, FLBrij Moudgil, UF-Gainesville, FLParvesh Sharma, UF-Gainesville, FLNian Wang, UF-Lake Alfred, FLClaudio Gonzalez, UF-Gainesville, FLMark Nelson, Echelon Corp.Jim Dukowitz, Technology Innovation GroupHarold Browning, Jim Syvertsen, CRDF04/21/23 25
