Antimicrobial resistance: use of bismuth-based compounds

8 February 2018

Professor Hongzhe Sun’s new research could potentially put a stop to deadly superbugs.

Antimicrobial resistance posed by “superbugs” is a major public health issue. Current clinical options for treating antibiotic resistant infections include increasing the prescribed antibiotic dose or using a combination therapy of two or more antibiotics. However, this might potentially lead to overuse of antibiotics, producing superbugs more resistant to antibiotics.

A research team led by Professor Sun Hongzhe (2010 Senior Research Fellowship) of the Department of Chemistry, Faculty of Science at the University of Hong Kong discovered an alternative strategy by repositioning colloidal bismuth subcitrate (CBS), an antimicrobial drug against Helicobacter pylori (H. pylori) -related ulcer.

They found the bismuth-based metallodrug to effectively paralyze multi-resistant superbugs, e.g. Carbapenem-resistant Enterobacteriaceae (CRE) and Carbapenem-resistant Klebsiella pneumoniae (CRKP) and significantly suppress the development of antibiotic resistance, allowing the lifespan of currently-used antibiotic to be largely extended. CRE and CRKP can cause deadly infections such as bacteremia, pneumonia, and wound infections.

CBS has been clinically used for a long period of time in many countries and regions including Mainland China and Hong Kong, significantly enhances the eradication rate of resistant H. pylori. Surprisingly, no bismuth-resistant strain has been reported even after a long-term use

The team is the first globally to link the “resistance-proof” ability of metallo-drug to the treatment of superbugs. This bismuth drug-based therapy looks set to become the last-line strategy against superbugs infections apart from the development of new antibiotics.

The findings were published in Nature Communications in January 2018 and a patent has been filed in the US for the discovery.

CRE is one of the three most dangerous superbugs of critical priority needs for new antibiotics. CRE resists almost all the clinically available antibiotics and spreads easily through person-to-person contact. If sepsis occurs, the death rate could be as high as 50%, according to the Centers for Disease Control (CDC) in the US.

The research team found that CBS and other relevant bismuth-based compounds could serve as potent inhibitors of NDM-1 (New Delhi Metallo-β-lactamase 1), one of the leading resistant determinants. This enzyme inhabits in bacteria and arms them with resistance to almost all commonly used beta-lactam antibiotics including the so-called “last resort” Carbapenem.

The NDM-1 carrying CREs is lethal and extremely difficult to treat. NDM-1 superbugs have now been disseminated to over 70 countries or regions across the world.

Through a series of tests on an NDM-1 Escherichia coli (E. coli), the team revealed that CBS can “tame” the superbug to almost sensitive strain which can be easily killed by Carbapenem antibiotics.

More importantly, this method allows the dose of antibiotics to be reduced by 90% to attain the same level of effectiveness, and the development of NDM-1 resistance to be significantly slowed down, which will largely extend the life cycle of currently used antibiotics.

In mouse model, NDM-1expression decreased by 2.7-fold (left) and resistance development slowed down by 4-fold (right)

Combination therapy of CBS and Carbapenem has been tested on mice and proved to prolonged life expectancy and raised the eventual survival rate of infected mice by more than 25 percentage points compared to Carbapenem monotherapy. The research team now concentrates on using CBS-based therapy in other animal infection models, e.g. urinary tract infection (UTI), hoping to offer a more extensive approach to combat with antibiotic resistant superbugs.

“We hope CBS-based combination therapy will open up a new horizon for the treatment of infection caused by superbugs, serving as a new and more economical therapy to solve the problem of antimicrobial resistance (AMR).”

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