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Antimicrobial resistance posed by “superbugs” has been a major public health issue of global concern. Drug-resistant infections kill around 700,000 people worldwide each year. The figure could increase up to ten million by 2050, exceeding the number of deaths caused by cancers, according to figures of the World Health Organization (WHO).
Current clinical options for treating antibiotic-resistant infections include increasing the prescribed antibiotic dose or using a combination therapy of two or more antibiotics. The current strategy might potentially lead to overuse of antibiotics, producing superbugs more resistant to antibiotics. Nevertheless, the development of antibiotic resistance far outruns the approvals of new antibacterial agents. While it may take a decade and cost an unusual high investment of USD 1 billion in average to bring a new drug to the market, generating resistance to a new drug only requires a short couple of years by bacteria. Scientists and clinicians are in desperate need to discover an economical, effective, safe alternative strategy to meet the global public health challenge of antimicrobial resistance.
Dr. Hongmin Zhang of Department of Biology, SUSTech led a joint research team. Professor Hongzhe Sun of the Department of Chemistry, and Dr. Richard Kao Yi-Tsun of the Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong (HKU) were key members of the research team. Together, they have discovered an alternative strategy by repositioning colloidal bismuth subcitrate (CBS), an antimicrobial drug against Helicobacter pylori (H. pylori) -related ulcer.
They found that 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, largely extending the lifespan of currently-used antibiotics. CRE and CRKP can cause deadly infections such as bacteremia, pneumonia, and wound infections.
The team is the first, globally, to link the “resistance-proof” ability of metallodrug 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. Since CBS is a US Food and Drug Administration (FDA)-approved drug, it will hopefully be rapidly ready for human clinical trials.
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 on WHO's list 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, as well as 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 that demonize common bacteria into CRE superbugs. This enzyme inhabits 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, which poses a great threat to public health and may drive the world to the cusp of a "post-antibiotic era." Scientists have reported on the presence of NDM-1 superbugs in over 70 countries or regions across the world.
Dr. Ho Pak Leung, Director of the HKU Carol Yu Centre for Infection ran a series of clinical tests on an NDM-1 Escherichia coli (E. coli) (denoted as NDM-HK). The team revealed that CBS could “tame” the superbug reducing it to an almost sensitive strain which can be easily killed by commonly used Carbapenem antibiotics.
More importantly, the brand-new therapy 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, largely extending the life cycle of currently used antibiotics.
In the mouse model of NDM-1 bacterial infection, combination therapy comprising CBS and Carbapenem significantly prolonged the 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.
Dr. Ho found the results very encouraging; saying: “There is currently no effective approach to overcome the NDM superbug. Bismuth has been used clinically for decades. Knowing that it can tame the NDM is like “a good rain after a long drought” for the scientific community.”
In a mouse model, NDM-1expression decreased by 2.7-fold (left), resistance development slowed down by 4-fold (middle), and the mutation frequency decreased by more than 100-fold.
Professor Sun said: “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 long-term use. 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).”
About Dr. Zhang’s research group
Dr. Zhang’s group studies the pathogenic mechanism of microbes through structural biology methods, screens and designs lead compounds based on the target structures. Previous studies in this group include the nucleoprotein of avian influenza H5N1, the pathogenic lipid-binding proteins in Penicillium marneffei and Aspergillus fumigatus (Mp1p and Afmp), collistin resistant superbug and so on. In recent years, Dr. Zhang’s group devotes much effort in the study of beta-lactam antibiotics resistant superbugs, focuses on the mechanism elucidation of antibiotics hydrolyzing enzymes, lead compound design, and screening based on high-resolution protein structures. These kinds of studies may set strong foundations for ultimately killing drug-resistant superbugs.
About Professor Sun Hongzhe's research team
Professor Sun is an internationally recognized expert of metallodrugs study, and his achievements have been published in leading scientific journals before, including Proceedings of the National Academy of Sciences, Journal of the American Chemical Society and Angewandte Chemie International Edition. His research interest resides in the interdisciplinary field of inorganic chemistry and biomedicine. He is the convener of the strategic research theme on "Integrative Biology" at the University of Hong Kong, with a multidisciplinary team of colleagues from chemistry, biology, and medicine. His team has made systemic, integrative and innovative achievements in Metallomics and Metallo-chemical biology, including mode of action of bismuth-based drug and development of new techniques/methods for metals/metalloproteins in cells and tissues. He determined the polymeric structure of CBS (De-Nol®) under the physiologically relevant conditions and had focused on mechanism-based metallo-drug design.
CBS is a non-toxic metallodrug and is usually served as an anti-ulcer component in the “cocktail” therapy against H. pylori-associated infections.
About β-lactam antibiotics
β-lactam antibiotics are the most widely used class of antibiotics for the treatment of bacterial infections, which include Penicillin derivatives (penams), Cephalosporins (cephems), Monobactams, and Carbapenems. Carbapenem has a broader spectrum of antimicrobial activity and is less affected by many common mechanisms of antibiotic resistance than other beta-lactam antibiotics, which has been used as the “last-resort” when patients received complicated infected by antibiotic-resistant bacteria. Once bacteria carry NDM-1, they will be extremely tough to kill even with a high dose of carbapenem.
The research paper published in Nature Communications