New Antibiotic Natural Products Against Various Drug-resistant Bacteria Identified

The rise of antibiotic resistance together with the lack of effective treatment has been noticed as a major threat to human health recently, mainly due to the overuse or misuse of antibiotics, and the problem is getting even worse because of global warming and increasing human contact through globalization.

Development of new antibiotics against drug-resistant bacteria, especially Gram negative Acinetobacter baumannii and Pseudomonas aeruginosa is considered to be an unmet medical need. As we know, the major constituent of bacterial cell wall, peptidoglycan, is synthesized by a bifunctional enzyme, called penicillin-binding protein, which consists of two enzymatic domains, transglycosylase (TGase) to synthesize the sugar backbone and transpeptidase to crosslink the peptides. To date, numerous transpeptidase-targeted antibiotics have been successfully developed, whereas only a few compounds have been identified to inhibit TGase but have never been developed into antibiotics for humans. Because of its accessible location and critical function, the bacterial TGase has been an attractive drug target to tackle the problem of antibiotic resistance.

 

Natural products have historically been recognized as a prolific and dependable source of antibacterial agents. Under the direction of Drs. Rachel Cheng and Chi-Huey Wong at the Genomics Research Center, Mr. Wei-Shen Wu, a Ph.D. student from National Defense Medical Center and the first author, devised a fast and effective affinity-based screen technology using immobilized TGase to isolate four potent inhibitors from fermentation broths. These compounds showed very strong antibiotic activities against a broad-spectrum of Gram-positive bacteria, including the drug-resistant strains of enterococci and staphylococci, and one of these compounds was very effective against such Gram-negative bacteria as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumonia, as well as their drug-resistant mutants. The result of this discovery was just accepted for publication in the Journal of American Chemical Society

 

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Figure:Affinity-based platform to isolate potent antibiotics from natural products

 

Encouraged by the potency of the compound against Acinetobacter baumannii, the research group has started collaboration to test if the antibiotics are effective against more bacterial clinical isolates and to solve the structure of TGase in complex with the inhibitors for further development of better antibiotics.

Link to the publication: http://pubs.acs.org/doi/abs/10.1021/jacs.7b13205

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