Anti-rheumatic drug offers therapeutic hope against superbugs

30 December 2020

A research team led by Professor Hongzhe Sun (Croucher Senior Research Fellowship 2010), of the University of Hong Kong (HKU), has discovered that repurposing an anti-rheumatic drug can re-sensitise “last-resort” antibiotics for treatment of infections caused by multidrug-resistant superbugs, including pneumonia, wound and bloodstream infections.

Sun, Chair Professor in the Department of Chemistry and Acting Director of the Research Division for Chemistry, works at the innovative edge of inorganic chemistry, biology and medicine. The breakthrough was made in studies carried out in collaboration with Dr Pak Leung Ho, Director of HKU’s Carol Yu Centre for Infection, Department of Microbiology, in the university’s Li Ka Shing Faculty of Medicine.

The findings provide insights into the development of inorganic pharmaceutics and a new therapeutic approach for superbug infections. They have been published in Nature Communications, and a patent filed in the US.

Antibiotics are used to kill bacteria and treat bacterial infections, with the most commonly administered being β-lactams antibiotics, such as cephalosporins and carbapenems.

However, their clinical efficacies have been greatly challenged as bacteria are now able to produce a resistant determinant, namely metallo-β-lactamases, that can hydrolyse nearly all β-lactams antibiotics.

As a result, “last line” antibiotic colistin re-emerged as a therapeutic option. However, with the emergence of mobilised colistin resistance enzyme, the efficacy of colistin has also been seriously compromised.

Given that the two resistant determinants have different structures and mechanisms, it has been difficult to adopt a general therapy for infections, implying that common infections with these “superbugs” may soon be untreatable.

In 2018, Sun’s research team found that a combination therapy consisting of an antibiotic resistance and antibiotic-resistance breaker offered promising options to narrow the gap between multidrug-resistant bacteria and the development of new antibiotics.

Following up with the previous research, the team found that gold drug auranofin, used to treat rheumatoid arthritis, could revive the potency of two highly effective antibiotics –meropenem and the previously mentioned colistin.

Through a series of screenings of an Escherichia coli (E. coli CKE), clinically collected by Ho in Hong Kong’s Queen Mary Hospital, they found that auranofin could entirely inhibit the hydrolytic activity of metallo-β-lactamases and disrupt functions of mobilised colistin resistance.

They also noticed that the dose of either meropenem or colistin could be lowered by 32~64 fold to achieve the same level of effectiveness against superbug E. coli CKE when used in combination with the anti-rheumatic drug.

A mouse model further showed that a combination therapy of auranofin and colistin to be highly effective in eradicating multidrug-resistant bacteria in peritonitis infection models. The antirheumatic drug restored the in vivo efficacy of colistin, with more than a 10-fold reduction in resistant determinants.

More significantly, all the mice that were systemically infected by superbug E. coli CKE were saved after a five-day course of treatment with the auranofin-colistin combination.

Sun said that considering well-recorded safety in humans, auranofin and related gold drugs used as a dual-inhibitor of metallo-β-lactamases and mobilised colistin resistance could greatly broaden therapeutic options in treating infections caused by multidrug-resistant superbugs.

Professor Hongzhe Sun is the Norman and Cecilia Yip Professor in Bioinorganic Chemistry and Chair Professor in the Department of Chemistry at the University of Hong Kong (HKU). He received his PhD from the University of London (Birkbeck) in 1996. After two years as a Research Fellow at the University of Edinburgh, he joined the Department of Chemistry at HKU as an Assistant Professor. He was promoted to Professor in 2007. Sun was appointed to his endowed professorship in 2019. He received his Croucher Senior Research Fellowship in 2010.

To view Professor Sun’s Croucher profile, please click here