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Bismuth-based gastric ulcer drug shows potential against superbugs

Jackey Suen
08 Mar 2018
From left: Dr Pak-Leung Ho, Dr Richard Yi-Tsun Kao, Prof Hongzhe Sun, Mr Runming Wang (PhD student), Dr Peng Gao

Bismuth-based antimicrobial drugs, conventionally used to treat Helicobacter pylori-related gastric ulcer, have shown potential in restoring antibiotic sensitivity to superbugs in a recent study conducted by The University of Hong Kong (HKU).

The study showed that the bismuth(III) compound colloidal bismuth subcitrate (CBS) restored the efficacy of meropenem against drug-resistant metallo-β-lactamase (MBL)–producing Enterobacteriaceae in vitro and in a mouse model. CBS was also found to slow down the development of higher-level resistance in bacteria harbouring New Delhi MBL 1 (NDM-1). [Nat Commun 2018, doi: 10.1038/s41467-018-02828-6]

The researchers observed a dose-dependent reduction in the enzymatic activity of NDM-1 and other related MBLs by up to >90 percent with CBS. When used in combination with CBS, the minimal inhibitory concentration of meropenem could be reduced by eight-fold.

“In other words, CBS was able to ‘tame’ superbugs and restore their sensitivity to antibiotics, so that they can be easily killed by commonly used carbapenems,” said study investigator Dr Pak-Leung Ho of HKU’s Department of Microbiology.

“NDM-1 superbugs are extremely lethal. In our study, all untreated mice died within 18 hours of infection. Compared with antibiotic therapy alone, CBS/antibiotic combination therapy improved the survival rate of infected mice by 25 percent [50 vs 25 percent],” Ho continued. “CBS/antibiotic combination therapy also slowed down the development of NDM-1 resistance by four-fold.”

“NDM-1 is one of the most widespread and threatening MBLs that binds to and hydrolyzes almost all β-lactam antibiotics with zinc(II) ion as a cofactor. Considering that MBLs are Zinc(II)-containing enzymes, their inactivation using metal compounds may represent a new approach for the development of MBL inhibitors,” explained study investigator Professor Hongzhe Sun of the Department of Chemistry, HKU.

“Most organic MBL inhibitors inactivate the enzyme through binding to the substrate site of specific types of MBLs, and are therefore unlikely to be developed as broad-spectrum inhibitors of MBLs,” Sun continued. “In contrast, bismuth(III) compounds irreversibly inhibit MBLs via a unique metal displacement mechanism. They inactivate MBLs through the replacement of zinc(II) ion cofactor by bismuth(III) ion at the active site. Based on this unique mechanism, we strongly suggest that bismuth(III) compounds can be developed as broad-spectrum MBL inhibitors.”

“Our study demonstrated the potential of repositioning bismuth(III) compounds as a new class of broad-spectrum MBL inhibitors,” the researchers concluded. “Bismuth(III) compounds have been in clinical use for a long time for H. pylori eradication, with negligible toxicity in humans. Surprisingly, no bismuth-resistant strain has been reported. The coadministration of this broad-spectrum MBL inhibitor and antibiotics will undoubtedly open a new horizon for the treatment of infection caused by MBL-positive bacteria. The combination treatment may also serve as an economical therapy to solve the problem of antimicrobial resistance.”

“We anticipate clinical trials to be initiated in the near future to evaluate the use of CBS in the treatment of superbug infection,” they added.

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