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New Protein Discovery Solves Myth of Bacterial Drug Resistance

Date: 
Thursday, December 31, 2015
Contact: 

Elsa Ming-tzu Shih | User Administration & Promotion Office, National Synchrotron Radiation Research Center | shih.elsa@nsrrc.org.tw | +886-3-5780281 ext. 8207

New findings on bacteria of Typhoid fever

An international team of Taiwan and Malaysia has discovered unprecedentedly a unique structure of an outer-membrane protein from bacteria that causes the contagious Typhoid fever. Chun-Jung Chen (NSRRC), Hong-Hsiang Guan (NSRRC) and their collaborators used the experimental stations at the Taiwan Light Source (TLS) in Taiwan and SPring-8 in Japan as a crucial process to determine this important structure. It took four years to figure out the 3D structure of ST50, the outer-membrane protein, from Salmonella Typhi. The research team discovered the key of how ST50 can excrete the antibiotics outside the pathogen and result in antibiotic resistance. The research results have been published in Scientific Reports.

The structure of outer-membrane protein of Salmonella Typhi. A “D-cage” located at the entrance captures the antibiotics before secretion outside the pathogen through the channel

Typhoid fever is a highly contagious bowel disease, which causes persistent high fever, dry cough, headache, stomach flu, intestinal perforation, hemorrhage, rashes, and even death. Over 21 million cases are reported globally and the disease resulted in about 200 thousand deaths each year. In Asia, it is prevalent particularly in Indonesia, China, Thailand, Vietnam, and the Philippines. Travelers could be infected with the disease during their travels.

This team discovered that the ST50 proteins, located on the surface of bacteria, equip a fascinating structure to function as an efflux pump, which excretes the antibiotics out of bacteria. A new discovered “D-cage”, which comprises six aspartic acids at the entrance of the pump, captures antibiotics and other poisonous metabolites or xenobiotics before these toxic elements can be transported out through the protein channel. Such a transport mechanism makes the bacteria drug-resistant.

Antibiotics are commonly used to kill bacteria, but currently it is less effective as expected due to drug resistance. Chen pointed out, “Now that we have revealed the structure of this efflux pump at resolution 2.98 Å, 300 thousand times smaller than the diameter of single hair, it could pave the way for the future development on anti- drug-resistant treatment.”

The new mechanism of the efflux pump. The ST50 on the membrane surface of Salmonella Typhi works as a pump and results in drug resistance. (1) The ST50 on the outer-membrane adopts a partially open form of the extracellular loop in the absence of efflux substrates. (2) The ST50 combines with the other two proteins and activate the efflux pump after the antibiotics enters the bacterium. (3) The D-cage at the periplasmic substrate entrance captures antibiotics and other poisonous metabolites or xenobiotics. (4) The toxic elements are transported out of the bacterium through the protein channel while the gate of three extracellular loops is open

Chen continued, “Traditional drug-development process from the scratch is a billion-dollar gamble. Scientists start with screening 5 to 10 thousand drug compounds. 250 drug candidates are subsequently selected for animal tests, and finally only less than 10 compounds enter the stage of human clinical trials. The process of a new drug discovery usually takes 0.8 to 2 billion USD and 1.5 decade, which is costly and inefficient. However, with the detailed structures of key proteins in pathogens analyzed by the synchrotron light, we can design the better structure-based target-drugs, which shortens the time and lowers the cost dramatically.”

Proteins are the origin of life, and synchrotron sheds light on them Proteins are the key components of life organisms and act as the executing machineries in cells. Each protein essentially folds into its own special structure and shape to reflect its unique function. Proteins could be the receptors on the cell membrane and the messengers among or inside the cells, responsible for signal transduction, energy transfer and function regulation.

“The 3D structures of proteins are the keys to understand the mechanisms of life processes. Among more than 100 thousand solved protein structures among the world, 86% of them were determined with the synchrotron light and the protein crystallography technique. In recent years, six Nobel prizes were given to scientists who conduct their researches using this technique,” Yuch-Cheng Jean, a beamline scientist at the NSRRC, mentioned.

The Taiwan Photon Source, constructed with 7 billion TWD in Taiwan, is inaugurated on January 25, 2015. The NSRRC is commissioning one of the phase-I beamlines, Protein Microcrystallography Beamline, since November 2015. It is scheduled to be open to domestic and international users in September 2016.

Read more about the research at http://www.nature.com/articles/srep16441

About the NSRRC

The NSRRC is a non-profit and research institute, funded by the Ministry of Science and Technology (MOST) in Taiwan, to provide two synchrotron light sources (1st: 1.5 GeV - Taiwan Light Source (TLS) and 2nd: 3 GeV – Taiwan Photon Source (TPS) ) for researchers in Taiwan and overseas to conduct frontier scientific experiments. The TLS consists of 25 beamlines and over 50 experimental stations. The TPS will accommodate ~40 beamlines (partly available for sponsor, co-sponsor, or customization per request). Currently, the NSRRC has over 2,000 users annually, the largest number of users among all large scaled scientific research facilities administrated under the MOST in Taiwan
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