Professor Xuechen Li: leading the way in the fight against superbugs

13 April 2018

One of the threats to human health in modern times is the rise of antibiotic resistant microbes.

Professor Xuechen Li (Croucher Senior Research Fellowship 2018) and his team have pioneered a technique using serine and threonine ligation, a method of protein chemical synthesis, allowing the structural modification of peptide-based antibiotics to discover novel antibiotics that have the potential to kill drug resistant bacteria.

Serine and threonine ligation

Development of solid phase peptide synthesis in the 1960s was a significant development. It allowed for the synthesis of polypeptides, a milestone in the field of biology and medicine. A substantial number of modern drugs are manufactured using peptide synthesis including antibiotics, anti-cancer agents, medications for diabetes, and heart conditions. However, solid phase peptide can synthesise only a limited number of amino acids, which led researchers to develop chemical ligation techniques to create longer peptides and protein chains.

Serine and threonine ligation, a tool for chemical synthesis of proteins in 2013, is chemo-selective with unprotected side chain peptides. Using a simple operational strategy, it can be used to combine shorter amino acids to form longer peptides, as well as synthesise cyclic peptides for therapeutics.

“With its development, the synthesis of several proteins in our lab which are otherwise difficult to obtain by biological methods, are producible. These synthetic proteins have allowed us to study their biological significance and medicinal properties,” said Li.

“Apart from peptide synthesis, serine and threonine ligation can manipulate the structure of proteins to increase the effectiveness of existing drugs and treatments. The immediate use of serine and threonine ligation was to synthesise peptide-based antibacterial drugs.”

Teixobactin

In 2015, US scientists discovered Teixobactin, a natural antibiotic previously unknown to medicine. With the capability to kill gram-positive bacteria, Teixobactin was pitted as a potential new antibiotic in the global fight against superbugs. However, Teixobactin was only in the early stages of development and undergoing investigations to develop a form with better drug profile. In 2016, Li’s team became one of the first in the world to complete the chemical synthesis of Teixobactin with in-house serine and threonine ligation technology. Up to now, his team has synthesised nearly 100 Teixobactin analogues, several of which showed improved antibacterial activities as compared to the original.

Successive laboratory and animal tests have shown this form of Teixobactin to be a highly potent new class of antibiotic against resistant microbes like MRSA (methicillin-resistant staphylococcus aureus), VRE (vancomycin-resistant Enterococcus), and multidrug-resistant Mycobacterium tuberculosis. This promising treatment comes at a time when existing medicines are becoming increasingly ineffective and patients needing life-saving surgeries, cancer therapies, or suffering immunosuppressive diseases that rely on antibiotics are at the risk of turning fatal, compromising our ability to treat both common illnesses as well as complicated conditions.

“Teixobactin’s new structure motif; which could be a basis for many novel antibiotic designs,” said Li “my team has discovered a derivative of Teixobactin with promising drug potential, however, it is still in preliminary stage and needs more research.

Daptomycin

Ideally, every several years after the use of an antibiotic in clinics, it should be improved and a second-generation drug should be developed to prepare for resistance. Daptomycin, a powerful antibiotic used to treat diseases caused by gram-positive bacteria, including MRSA, complex skin conditions and infections that have entered the bloodstream, was first approved by FDA in 2003, but resistance to the drug has already appeared in hospitals.

Li’s team has been working on second-generation drug and developed the first total chemical synthesis of daptomycin using serine and threonine ligation, and has already synthesised more than 100 analogues.

“We have found a new analogue that shows a better drug profile than the existing daptomycin to the resistant strain. It is very promising, we have already conducted animal tests and about to start pre-clinical trial,” said Li. “this is why serine and threonine ligation is important, not only for antibiotic research but synthesis and access to protein enables us to investigate their biological significance and answer fundamental medical questions.”

Challenges

In 2017, for the first time, WHO published a list of 12 antibiotic resistant bacteria with an aim to promote research and development of new drugs to address the burgeoning public health catastrophe.

“Drug resistance is spreading globally and rapidly, however development of new antibiotics is moving at a snail’s pace, and therein lies the problem,” said Li. “many superbugs are developing resistance to available drugs and as a result, even in the 21st-century people are dying of bacterial infections.”

Interdisciplinary approaches have strengthened research and have led to promising new developments. However, continued lack of investment in antibiotic studies poses a major challenge and is delaying drug discovery, according to Li.

“Pharmaceutical companies do not seem to be so interested in AMR, unlike anti-cancer research,” added Li. “But given its huge public need, as an academic researcher, I continue to pursue it and eventually hope to contribute to the society.”

Seth Herzon, Professor of Chemistry at Yale University commented, “Li’s work will extend our capabilities to synthesize, modify, and evaluate complex polypeptide antibiotics. On an applied level, the work could lead to the identification of new antibiotics, which would impact millions of lives.”


Xuechen Li was recently promoted to Professor of Department of Chemistry at the University of Hong Kong. He obtained his Bachelor of Science in Chemistry from Nankai University, MSc from the University of Alberta and PhD from Harvard University in 2006. He was a recipient of Croucher Senior fellowship in 2018. He received Distinguished Faculty Award in 2016 from the Chinese-American Chemistry & Chemical Biology Professor Association. In 2014 he was awarded with Outstanding Young Research Award from the University of Hong Kong and was the recipient of Wuxi PharmaTech Life Science and Chemistry-Scholar Award in 2013.


To view Prof Li’s Croucher profile, please click here