In the relentless battle 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 serves as an essential nutrient that bacteria utilise for various cellular processes, including DNA replication, energy production, and other vital functions. In essence, iron is like a ‘food’ for bacteria.

Building upon this understanding, a research team led by Professor Hongzhe SUN from the Department of Chemistry, The University of Hong Kong (HKU), introduced a ‘Dual Trojan Horse’ strategy, where a metal-based-drug and sideromycins, a class of antibiotic structurally resembling iron, work together in combating antibiotic-resistant bacteria. This approach allows these antibiotics to be delivered into bacterial cells through a pathway that mimics iron uptake. When bacteria encounter sideromycins, they are deceived into believing they are acquiring iron, prompting them to usher these compounds into their cells. This strategy not only enhances the effectiveness of sideromycins but also prolongs their lifespan, marking a significant advancement in our battle against antibiotic resistance. These promising results were successfully replicated in a live mice model, introducing an innovative strategy to combat antimicrobial resistance, offering hope in the fight against superbugs in clinic. These findings have recently been published a in Nature Communications entitled ‘Metallo-sideromycin as a dual functional complex for combating antimicrobial resistance (AMR)’.

‘We are short of new antibiotics, and infection caused by resistant bacteria (i.e. superbugs) may lead to another pandemic. We have uncovered a dual Trojan Horse strategy to restore antibiotics activity, such as cefiderocol, and hope to provide a novel arsenal for combating antimicrobial resistance,’ commented Professor Sun.

Research Background
Antimicrobial resistance (AMR) in bacterial infections has emerged as a significant global health concern. The overuse and misuse of existing antibiotics have accelerated the acquired drug resistance in bacteria, resulting in resistance to almost all antibiotics used in clinical settings across various bacteria strains.

Gram-negative bacterial infections, such as those caused by Pseudomonas aeruginosa, pose significant challenges in treatment due to their complicated structure. For example, the high resistance of P. aeruginosa against conventional antibiotics can be attributed in part to the limited permeability of the outer membrane (OM) and the expression of ‘efflux pump’, specialised proteins within bacteria that actively remove antibiotics, thus reducing their effectiveness. These factors collectively impede the accumulation of antibiotics at the bacterial target site.

Gram-negative bacteria, including Pseudomonas aeruginosa, can cause a range of 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 lead to skin and soft tissue infections, bloodstream infections (sepsis), and infections in wounds or surgical sites. In severe cases, these infections can be particularly challenging to treat due to the bacteria‘s resistance to antibiotics, making them a significant health concern. For these reasons, there is now an urgent need for both new antibiotic discovery and other modifications or strategies to enhance or prolong the antibacterial activity of existing clinical antibiotics.

Sideromycin is a novel type of antibiotic where the parent antibiotics or prodrug incorporates a siderophore molecule that utlises iron transport system for delivery. This incorporation enables the active transport of the antibiotic into bacterial cell through nutrient pathways. Cefiderocol (FetrojaÒ) is a recently FDA-approved sideromycin antibiotic in 2019. The antibacterial activity of cefiderocol is improved under the iron-deficient condition because of the enhanced uptake of cefiderocol, with a component of catechol, which coordinate with iron and facilitate the transportation of cefiderocol-iron complex in P. aeruginosa.