Resistance to antibiotics and the consequent evolution of "superbugs" is posing a serious dilemma for medical professionals and pharmaceutical researchers. While more and more microbes are becoming resistant to available antibiotics, fewer and fewer new drugs are being approved for use. Such a situation has created an urgent demand for different ways of looking at the development of new antibiotics. A research team led by Dr. Tsung-Lin Li, an Assistant Research Fellow at the Genomics Research Center, recently accidentally stumbled upon a new strategy for producing more effective antibiotics, by slightly changing the chemical structure of an existing antibiotic to expanding microbial enzymatic activities. Their findings were published online in the top journal Nature Chemical Biology on April 10, 2011.

Many antibiotics in common use today are semi-synthetically produced. Originally, however, these compounds were isolated from microbes (such as bacteria and fungi). In the natural setting, microbes use such compounds to defend themselves from other microorganisms. One class of antibiotics, called glycopeptide antibiotics, such as vancomycin and teicoplanin, are usually used by physicians as drugs of last-resort because, in addition to destroying bacteria, they are also toxic to human cells. In recent years, however, there have been many reports of bacterial resistance, even against these drugs.

Dr. Li and his colleagues looked into the biosynthesis of a glycopeptide antibiotic called A40926, the natural defense product of the bacterium Nonomuraea. They tinkered with the molecular machinery responsible for the compound's natural production by slightly altering the enzymes involved in the process. They ended up with several compounds that differed chemically, only slightly from the original antibiotic. These analogs were tested in mice infected with antibiotic-resistant Enterococcus bacteria and one, in particular, was found very effective at reducing the bacteria counts.

The finding represents a possible new approach in the search for means to produce new drugs to fight bacteria, and researchers hope that in the future such biosynthetic engineering can be applied to other microbe-antibiotic systems. "This approach allows access to new classes of products that would be extremely difficult to obtain by conventional organic synthesis and that offer improved and complementary profiles for antimicrobial drug discovery efforts." said Dr. Li.

The discovery is a particularly important achievement for the first author of the article, Mr. Yu-Chen Liu, who has yet to obtain his PhD. Mr Liu is a doctoral student of Institute of Biochemical Sciences at National Taiwan University, and a student of the Chemical Biology and Molecular Biophysics (CBMB) program, part of Academia Sinica's Taiwan International Graduate Program (TIGP).

The full-text of the paper entitled "Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds" is available at the Nature Chemical Biology website at: http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.556.html

The complete list of authors is: Yu-Chen Liu, Yi-Shan Li, Syue-Yi Lyu, Li-Jen Hsu, Yu-Hou Chen, Yu-Ting Huang, Hsiu-Chien Chan, Chuen-Jiuan Huang, Gan-Hong Chen, Chia-Cheng Chou, Ming-Daw Tsai and Tsung-Lin Li.

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