Despite hundreds of millions of years of divergent evolution, almost all plants, animals and pathogens share some common biochemical fundamentals and strategies for environmental defense. This makes botany a rich source of useful and compatible compounds for the control of pathogens in animals. The use of functional biochemistry from the plants has long been the basis for traditional and herbal medicines and often considered less likely to trigger unwanted immunological responses between less genetically distant species within the same phyla than highly purified large complicated proteins or polymers.
Immune systems of most of the higher organisms protect from infection with defenses of increasing specificity. The simplest is a physical barrier that prevents pathogens, such as bacteria and viruses, from entering the organism. Plants and animals also have innate immune systems that are either genetically coded responses to specific pathogens, or various non-specific responses to pathogen chemistries.
Plants typically have a two branched immune system. The first recognizes and responds to molecules common to many classes of microbes, including non-pathogens, by increased expression of ROS (Reactive Oxygen Species) generating enzymes capable of initiating oxidative bursts, but such direct oxidative response is energy costly and must be strictly regulated to prevent autotoxicity. Many pathogenic microorganisms (bacteria, fungi, protozoa) are equipped with peroxidases or catalases as countermeasures against such ROS bursts. The second branch of the innate immune system is the multi-component wound response as described above initiated by the reaction between quinonic compounds and amino acids when cells are damaged. These compounds are usually compartmentally separated and do not cooperate in living systems. In plants, cellular disruption causes various phenol compounds and reactive oxygen species to come into contact with polyphenol oxidases (PPO), oxidizing the phenol compounds to form quinonic compounds that aggressively associate with each other and amino acids of the cells or any microorganisms present. This effects many physiologic phenomena, such as browning or discoloring of foods, precipitation of proteins, germicidal activity, astringency, changes in food digestibility and more.
Polyphenol oxidation in plant systems generates oxidized-polyphenols (also referred to as o-polyphenols, oxidized biopolymers, polyquinones and quinonic compounds) with a multiplicity of quinonic groups that are capable of covalent bonding. Once formed, the high affinity o-polyphenols spontaneously form covalent intra- and inter-chain cross-links that condense proteins far more aggressively than hydrogen bonds characteristic of non-oxidized polyphenols. In plant systems, o-polyphenols cross link damaged cell proteins to form a refractory shield between the healthy tissues and further assault. They also prevent pathogen propagation by aggressively binding to their metabolic pathways, disabling virulence enzymes and arresting pathogen motility.
Higher vertebrates possess an additional layer of protection, the adaptive immune system, which allows for a stronger immediate immune response to previously encountered pathogens. The aggregation of smaller molecules on the pathogen creates large complexes with an increased antigenicity of the pathogen to the host immune system. Each pathogen is “remembered” by a signature antigen. Should a pathogen infect the body more than once, these specific memory cells are used to quickly and efficiently eliminate it; however, these tailored responses can take many days to develop. In the interim, primary defense against newly encountered pathogens, especially in infection of immunologically deficient or immature animals relies solely on the innate immune systems and often is associated with negative physiologic responses such as diarrhea, vomiting, fever, inflammation, etc. Such systemic responses to infection are the expression of the very large numbers of immune effectors that can be extremely metabolically expensive, even fatal to the host.
One of the most common dangers associated with an unchecked systemic response by the innate immune system is diarrheal dehydration triggered by infectious diseases or parasites. Diarrheal dehydration affects over 2 billion people each year and is the most common cause of death for Third World infants, responsible for over 1.5 million deaths per year. Besides re-hydration, most efforts to treat diarrhea have focused on increasing human mucosal immunity by modulating systemic immune responses, such as by using intestinal motility reducing drugs, mucous permeability modifiers or antibiotic therapies. These approaches have limited success but introduce undesirable risks of side effects, pathogen resistance, or physiologic senescence.
There is constant commercial demand for botanical alternatives to antibiotics and synthetic chemical disinfectants for the control of disease associated with water, surface, and food borne pathogens. The explosive rise in antibiotic resistant diseases has been associated with the overuse of antibiotics in both humans and livestock. Many regional governments and international health organizations have called for phase out of unnecessary antibiotic use, especially in livestock feeds where they are used sub-therapeutically to enhance growth. To date, it is widely recognized that there are few cost effective and environmentally sound alternatives for the safe control of pathogens. Decades of research on plants as sources of new antimicrobials has primarily focused on mechanical or solvent extraction of specific plant compounds and has not been successful in generating compositions with potency, safety, user preference and environmental profile necessary to match the performance of current antibiotics and germicides.
USPTO Backgrounds
USPTO Backgrounds