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United States Department of Agriculture

Agricultural Research Service

Research Project: DEVELOPING GENETIC BIOTECHNOLOGIES FOR INCREASED FOOD ANIMAL PRODUCTION, INCLUDING NOVEL ANTIMICROBIALS FOR IMPROVED HEALTH & PRODUCT SAFETY

Location: Animal Biosciences and Biotechnology Laboratory

Title: Triple-acting antimicrobial treatment for drug-resistant and intracellular Staphylococcus aureus

Authors
item Becker, Stephen
item Roach, Dwayne
item Chauhan, Vinita -
item Shen, Yang -
item Foster Frey, Juli
item Powell, Anne
item Buchannan, Gary -
item Lease, Richard -
item Mohammadi, Homan
item Harty, William
item Simmons, Chad
item Schmelcher, Mathias -
item Camp, Mary
item Shields, Kelly -
item Dowd, Megan -
item Dong, Shengli -
item Baker, John -
item Sheen, Tamsin -
item Doran, Kelly -
item Prichard, David -
item Almeida, Raul -
item Nelson, Daniel -
item Marriott, Ian -
item Lee, Jean -
item Donovan, David

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: April 1, 2014
Publication Date: N/A

Technical Abstract: Multi-drug resistant bacteria are a persistent problem in modern health care, food safety and animal health. There is a need for new antimicrobials to replace over-used conventional antibiotics. Staphylococcus aureus (S. aureus) is a notorious pathogen for both animal and human health with multi-drug resistant strains highly prevalent. This pathogen has also evolved another way to evade antibiotic treatment by invading and residing intracellularly within animal cells. New treatments that reduce resistance development and tackle intracellular pathogens are sorely needed. We have identified three enzyme activities that cleave the cell wall peptidoglycans of S. aureus in three unique regions. Any one of the three enzymatic activities can lyse the cells when exposed extracellulary. When fused, these three enzyme domains maintain each of their activities in the final triple-acting fusion. We have shown that these triple-acting enzyme constructs greatly reduce resistance development compared to the parental enzymes alone and are effective at reducing S. aureus nasal colonization by 97%. We also show that when these enzymes (single, double or triple domain harboring) are fused to protein transduction domains, they enter animal cells and reduce the intracellular load of the pathogen up to 97% in three different cell types from three different species. The effect is maintained in two different animal models (osteomyelitis and mastitis of mice) as well as staphylococcal biofilms. The findings of this work identify the necessary components and methodology for generating multiple domain fusions with elements to address intracellular and multi-drug resistant pathogens. These findings will also aid scientists in the development of these and similar molecules as commercializable antimicrobials for use in animal production, animal and human health and food safety.

Last Modified: 11/22/2014
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