Dr Xuechen Li of HKU Department of Chemistry and his research team, together with collaborators in University of Central Florida (Dr Yu Yuan), USA and the Hong Kong Polytechnic University (Dr Sheng Chen), reported their studies on the synthesis of a newly-discovered "game-changing" antibiotic, teixobactin, in Nature Communications recently. This underlies potential application and development of the next-generation teixobactin-based antibacterial drugs.
Dr Xuechen Li (second from the left in the first row) and his teixobactin project-team at HKU Department of Chemistry (The University of Hong Kong)
Antimicrobial resistance is on the rise globally and has become a serious threat to human health. Methicillin- resistant Staphylococcus aureus (MRSA) has emerged as one of the most important pathogens, both in hospital and community-acquired infections. It is considered one of the most important superbugs in Hong Kong as it is extremely infectious and has a high mortality rate.
To avoid further aggravation of resistance-related problems, misuse and overuse of antibiotics should be prevented to minimise the emergence of drug-resistant organisms. At the same time, development of novel antibacterial and anti-resistant agents should be actively pursued. Although there is an urgent public need for new antibacterial drugs, very few pharmaceutical companies are interested in investing in the development of these, owing to the lower profit margin compared to some other medicines. That no new antibiotics have been introduced to the market over the last decade is evidence of this.
The team led by Dr Xuechen Li has been continuingly working on the development of new antibiotics for the past seven years. In 2013, it developed the first chemical synthesis of an antibiotic daptomycin, which enabled researchers to search for the next-generation daptomycin-based antibiotics.
Recently, his team has had further success by developing a chemical strategy to synthesise another antibiotic, teixobactin, which was discovered last year by researchers in the USA, and was considered a breakthrough in antibacterial drug research (Nature, 2015, 517, 455).
Teixobactin can kill a range of pathogens without detectable resistance, including methicillin-resistant MRSA, vancomycin-resistant Enterococcus (VRE) and Mycobacterium tuberculosis.
As promising as it is, teixobactin is not perfect yet as a drug and can be further improved for its clinical properties via structural modification. In the history of antibacterial drug development, modification of the lead compound has successfully led to many generations of improved penicillin-based antibiotics. Indeed, it is only through chemical synthesis and medicinal chemistry that one can flexibly modify the teixobactin structure to generate various teixobactin derivatives from simple materials. Thus, the development of a strategy to chemically synthesise teixobactin and its derivatives has drawn a lot of attention, with more than 15 research groups from different countries striving to develop a chemical strategy to achieve this.
Collaborating with another chemist from University of Central Florida, USA, the HKU team has completed the chemical synthesis of teixobactin, from which it has also generated 10 teixobactin analogues with promising properties (US provisional patent filed). The strategy the team developed is very efficient and can generate many teixobactin derivatives in a fast and combinatory manner. Now they are running at a full speed with an aim to synthesize more 100 different teixobactin derivatives within two years to search for analogues with improved pharmacological properties for clinical development.
Read CRJ’s articles on antimicrobial resistance in issue 12:4, out soon.