{"id":549,"date":"2021-12-02T15:29:08","date_gmt":"2021-12-02T21:29:08","guid":{"rendered":"https:\/\/uwm.edu\/drug-discovery\/?page_id=549"},"modified":"2026-02-25T08:21:23","modified_gmt":"2026-02-25T14:21:23","slug":"development-of-antibiotic-alternatives-for-disease-management","status":"publish","type":"page","link":"https:\/\/uwm.edu\/drug-discovery\/projects\/development-of-antibiotic-alternatives-for-disease-management\/","title":{"rendered":"Development of antibiotic alternatives for disease management"},"content":{"rendered":"\n
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The organic production of apples and pears in the United States is challenged by the lack of adequate organic disease control measures. Fire blight<\/a>, caused by the bacterial pathogen Erwinia amylovora<\/em>, is one of the top two most devastating diseases for apples and pears. Damage from fire blight come in two ways. First, the fire blight infection on flowers, shoots, and leaves significantly reduce the yield. Typical yield reduction caused by fire blight ranges between 20% and 100%. Second, once entering the trees, the fire blight pathogens can systemically migrate through xylem to trunks and rootstocks, leading to tree death.<\/p>\n\n\n\n

Despite the tremendous damage posed by fire blight, the control options for organic growers are minimal. One crucial factor limiting organic tree fruit production is the lack of effective organic management options for plant diseases.  The human antibiotic streptomycin is by far the most effective (up to 90% control) and widely-used material for fire blight control in the United States. The intensive, long-term use of streptomycin has led to the evolution of streptomycin resistance in the pathogen populations.  Since the first report in California in 1971 (Miller 1972<\/a>), streptomycin resistance in E. amylovora has been commonly detected in almost all apple-producing regions in the United States, such as Washington (1972), Michigan (1990), and has been recently detected in New York (2003) (Coyier 1975<\/a>; Chiou and Jones 1993<\/a>; Russo 2008<\/a>). The impact of streptomycin resistance is dramatic, both from the perspective of economic loss as well as the impact to environmental and human health.<\/p>\n\n\n\n

For over 20 years, the Yang lab has worked on new management tools as an alternative to human antibiotics in plant disease management.  We identified natural compounds and their derivatives that can control fire blight and other agricultural crop diseases.<\/p>\n\n\n\n

Virulence inhibitors (VIs) are promising alternatives to antibiotics<\/h2>\n\n\n\n

The biggest limitation of antibiotics is the lack of sustainability due to development of antibiotic resistance. The motivation for bacteria to develop antibiotic resistance is the huge selective pressure that the antibiotics impose on the survival of bacteria. Antibiotics target essential cell metabolism processes and intend to kill bacteria. Thus, upon treatment, bacteria are pressured to persist, mutate, and eventually escape the antibiosis by developing or acquiring resistance through mutation or horizontal gene transfer.<\/p>\n\n\n\n

Virulence inhibitors (VIs) are compounds that inhibit the expression of virulence genes but do not affect the survival of bacterial pathogens. Thus, there is no direct selective pressure for bacteria to mutate to resist the VI compared to traditional antibiotics. However, as virulence genes are essential for the pathogens to cause infection, \u201cshutting off\u201d the virulence genes can effectively prevent disease from occurring. Additionally, unlike antibiotics that kill both pathogens and the non-pathogens without any selection, VIs only target the pathogens that contain the virulence genes and thus do not affect the non-pathogenic environmental bacteria. The target specificity of VIs further reduces the likelihood of resistance development and spread. To successfully cause host cell death, suppress host immunity and induce disease symptoms, the fire blight pathogen E. amylovora<\/em> developed several virulence factors. Among them, the type III secretion system (T3SS) is considered the most critical virulence factor in the disease development of E. amylovora<\/em>. The T3SS is a needle like structure that translocates virulence proteins from the bacterial cells into the host cells.  The translocation of these virulence proteins results in host cell death and disease development. Deletion of the T3SS genes renders complete loss of pathogenicity.  In this study, we screened plant phenolic compounds and their derivatives for virulence inhibitors; potent compounds were identified and show reduced fire blight disease incidences at a similar effectiveness level to the antibiotics in two years of field trials.<\/p>\n\n\n\n

Develop Biological control agents (BCAs) that can effectively control crop diseases<\/strong><\/h2>\n\n\n\n

In this project, we have obtained the first large collection of microbes from different natural environments in Wisconsin and other US states. A total of ~40,000 microbial isolates were screened to identify biocontrol agents on fire blight control. The living bacterial cells and the crude extract of a Pseudomonas<\/em> sp. T3-07 showed excellent inhibition of E. amylovora<\/em>. To understand the mechanism and evaluate the robustness of T3-07 as a biocontrol agent, we characterized the active metabolites produced from T3-07 responsible for the antimicrobial activities against E. amylovora<\/em>. The bacterial metabolites were purified with pre-HPLC and analyzed by MS, NMR, and X-ray crystal structure analysis. One highly potent novel compound, RejuAgro A, that inhibits E. amylovora<\/em> was identified. The efficacy of RejuAgro A (MIC 5 \u00b5g\/ml) is four times higher than streptomycin (MIC 20 \u00b5g\/ml) on E. amylovora<\/em> streptomycin-sensitive strain 1189.  For the streptomycin-resistant strains of E. amylovora<\/em>, the MIC of RejuAgro A is 10 \u00b5g\/ml compared to 100 \u00b5g\/ml to strains CA11 and DM1, and 2000 \u00b5g\/ml to strain 88, respectively.  RejuAgro has high inhibiting capabilities compared to commercial products. RejuAgro A was found to inhibit 21 agricultural crop pathogens, of which nine pathogens across seven crops are of high commercial interest, including diseases on apple, citrus, tomato, walnuts, peaches, potato, and rice.  RejuAgro A was also found to be highly potent to six fishery pathogens with the minimum inhibitory concentrations ranging from 0.39 \u00b5g\/ml to 12.5 \u00b5g\/. The results are promising for developing a potential commercial product in aquaculture.<\/p>\n\n\n\n

Patents<\/strong><\/h2>\n\n\n\n

US 9,260,382 B2 METHODS OF REDUCING VIRULENCE IN BACTERIA, February 16, 2016<\/a><\/p>\n\n\n\n

CN  102883602 B CN  METHODS OF REDUCING VIRULENCE IN BACTERIA, July 18, 2017<\/a><\/p>\n\n\n\n

US 17\/063,540 PSEUDOMONAS STRAINS AND THEIR METABOLITES TO CONTROL PLANT DISEASES, October 5, 2020<\/p>\n\n\n\n

Global PCT US20\/54303 PSEUDOMONAS STRAINS AND THEIR METABOLITES TO CONTROL PLANT DISEASES, October 5, 2020<\/p>\n\n\n\n

US 17\/494,068 PSEUDOMONAS STRAINS AND THEIR METABOLITES TO CONTROL FISH DISEASES, October 5, 2021<\/p>\n\n\n\n

PCT US21\/53482 PSEUDOMONAS STRAINS AND THEIR METABOLITES TO CONTROL FISH DISEASES, October 5, 2021<\/p>\n<\/div>\n\n\n\n

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