HONG KONG SAR – Media OutReach – September 22, 2023 – In the fierce fight against antibiotic-resistant superbugs, science continues to unveil ingenious strategies to address their vulnerability. Like other bacteria, superbugs have a unique weakness: their dependence on iron for growth and survival. Iron is an essential nutrient that bacteria use for various cellular processes, including DNA replication, energy production, and other vital functions. Essentially, iron is like “food” for bacteria.
Professor Hongzhe SUN’s research team (second from left) from the Department of Chemistry, University of Hong Kong.
Building on this understanding, a research team led by Professor Hongzhe SUN from the Department of Chemistry at the University of Hong Kong (HKU), introduced a “double Trojan” strategy, in which a drug based on Metal and sideromycins, a class of antibiotics that resemble iron in structure, work together in the fight against antibiotic-resistant bacteria. This approach allows these antibiotics to be delivered into bacterial cells through a pathway that mimics iron absorption. When bacteria encounter sideromycins, they mistakenly believe they are acquiring iron, prompting them to introduce these compounds into their cells. This strategy not only improves the effectiveness of sideromycins, but also extends their shelf life, marking a significant step forward in our fight against antibiotic resistance. These promising results were successfully reproduced in a live mouse model, introducing an innovative strategy to combat antimicrobial resistance, offering hope in the fight against superbugs in the clinic. These results were recently published in
Natural communications entitled “Metallo-sideromycin as a dual-function complex to combat antimicrobial resistance (AMR)”.
“We are running out of new antibiotics and infections caused by resistant bacteria (i.e. superbugs) could lead to another pandemic.” We discovered a double Trojan horse strategy to restore the activity of antibiotics, such as cefiderocol, and hope to provide a new arsenal to combat antimicrobial resistance,” commented Professor Sun.
Research background
Antimicrobial resistance (AMR) in bacterial infections has become a significant global health problem. Overuse and misuse of existing antibiotics have accelerated the acquisition of drug resistance in bacteria, resulting in resistance to almost all antibiotics used in clinical settings across various bacterial strains.
Gram-negative bacterial infections, such as those caused by
Pseudomonas aeruginosa, pose significant processing challenges due to their complex structure. For example, the high resistance of
P. aeruginosa against conventional antibiotics may be attributed in part to the limited permeability of the outer membrane (OM) and the expression of “efflux pumps,” specialized proteins within bacteria that actively remove antibiotics, thereby reducing their effectiveness. These factors collectively prevent accumulation of antibiotics at the bacterial target site.
Gram-negative bacteria, including
Pseudomonas aeruginosa, can cause various infections in humans. These infections often affect the respiratory system, leading to pneumonia or lung infections, as well as urinary tract infections. They can also cause skin and soft tissue infections, blood infections (sepsis), and infections of wounds or surgical sites. In severe cases, these infections can be particularly difficult to treat due to the bacteria’s resistance to antibiotics, making them a significant health problem. For these reasons, there is now an urgent need for the discovery of new antibiotics and other modifications or strategies to improve or prolong the antibacterial activity of existing clinical antibiotics.
Sideromycin is a new type of antibiotic in which the parent antibiotic or prodrug incorporates a siderophore molecule that uses the iron transport system for its delivery. This incorporation allows the active transport of the antibiotic into the bacterial cell via the nutrient pathways. Cefiderocol (FetrojaÒ) is a sideromycin antibiotic recently approved by the FDA in 2019. The antibacterial activity of cefiderocol is enhanced in iron deficiency due to the increased absorption of cefiderocol, with a catechol component, which coordinates with iron and facilitates transport. of the cefiderocol-iron complex in
P. aeruginosa.
Although the resistance frequency of
P. aeruginosa to cefiderocol is much weaker than its parent antibiotic ceftazidime, resistance to cefiderocol has inevitably developed recently in several strains of Gram-negative bacteria, for example in Carbapenem-Resistant
Escherichia
coli strains and
Acinetobacter baumannii in burn infections. Cefiderocol resistance was linked to β-lactamase production, siderophore receptor mutations, efflux pump expression, and the combination of these mechanisms.
Metal compounds have been used for years as promising antimicrobial agents and exhibit a low frequency of resistance because they have multi-target modes of action. Bismuth (Bi3+) compounds showed potent antibacterial properties against bacteria that had become resistant to various antibiotics. These bismuth compounds act as versatile inhibitors of a group of enzymes called metallo-β-lactamase inhibitors, which are involved in antibiotic resistance. Gallium(Ga3+) also provides antibacterial activities by disrupting iron (Fe3+) absorption system and iron homeostasis.
Interestingly, catecholate siderophores exhibit exceptionally high affinity not only for iron (Fe3+), but also to metals like bismuth (Bi3+) and gallium (Ga3+). These metals behave similarly to iron when they bind to catecholate molecules. These special catechol-metal combinations have been observed to accomplish two things: they can compete with iron to get inside bacterial cells, and they can mimic iron in biological systems, thereby disrupting important iron functions. . Thus, the team proposes a dual “Trojan horse” strategy to simultaneously “introduce” antibiotic sideromycins and metal ions via the siderophore receptor, the same pathways used by bacteria to seize nutrients, leading to an effect synergistic against bacterial infections.
Main findings
In this study, the team demonstrated that a bismuth-based drug (CBS) could improve the potency of cefiderocol against
P. aeruginosa in both laboratory experiments
(in vitro) And
living animal
test
(live). This improvement included improved efficacy against biofilm formation by cefiderocol, suppression of the development of high-level bacterial resistance to cefiderocol, and restoration of the effectiveness of cefiderocol against resistant bacteria.
P. aeruginosa strainsincluding those isolated from clinical cases involving real patients.
Such phenomena are probably due to competition from Bi3+ with Fe3+ to cefiderocol, resulting in decreased Fe absorption3+ and increased absorption of antimicrobial Bi3+/Georgia3+. This competition disrupts the integrity of the bacterial membrane, making the antibiotics more permeable.
THE
in vitro interaction of Bi3+ with cefiderocol was confirmed by UV-vis spectroscopy and MS spectrometry, analytical techniques which confirmed the interaction between Bi3+ and cefiderocol, resulting in the formation of a 1:1 complex of Bi3+-cefiderocol. Metallo-sideromycin could not only improve the effectiveness of sideromycin, but also extend the effective life of this type of antibiotics. Their animal studies further validated the effectiveness of the approach. It is worth studying other sideromycins and metals in more detail, in order to thoroughly explore the potential of metallo-sideromycins in the treatment of infections caused by drug-resistant bacterial pathogens. The research team has filed a patent for this discovery.
About the research team
This study was jointly carried out by the Department of Chemistry, the Department of Microbiology and the Carol Yu Center for Infection of the University of Hong Kong. Ms. Chenyuan WANG and Dr. Yushan XIA are the co-first authors of this article. Other members participating in the research include Dr Hongyan LI, Dr Patrick H TOY, Dr Runming WANG, postgraduate student Ms Jingru LI and Mr Chun-Lung CHAN from the Department of Chemistry, Professor Richard Yi -Tsun KAO from the Department of Microbiology, Professor Pak-Leung HO from the Carol Yu Center for Infections. This research was supported by the Research Grants Council of the Hong Kong SAR (R7070-18, 17308921, 2122-7S04), the Medical and Health Research Fund of the Health Bureau of the Hong Kong SAR ( CID HKU1-13) and the University of Hong Kong. Kong (URC (202107185074) and Norman & Cecilia Yip Foundation).
About Professor Hongzhe Sun
Professor Hongzhe Sun is the Norman & Cecilia Yip Professor of Bio-Organic Chemistry and Full Professor of Chemistry at the University of Hong Kong. His research focuses on metalloproteomics and metallomics, antimicrobial and antiviral agent discovery, and inorganic chemical biology. Dr. Hongyan Li is a research assistant professor in the Department of Chemistry, University of Hong Kong.
To view the research paper “Metallo-sideromycin as a dual-function complex to combat antimicrobial resistance”, please visit:
https://www.nature.com/articles/s41467-023-40828-3
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https://www.scifac.hku.hk/press
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