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A Silver Lining In Antimicrobial Resistance: How Silver Ions Target Proteins in Staphylococcus aureus

Scientists from the University of Hong Kong have discovered that silver ions functionally disrupt key proteins and biological pathways in Staphylococcus aureus, validating its efficacy as an antibiotic adjuvant to combat antimicrobial resistance.

Claiming about 700,000 lives annually and foreseen to cause 10 million deaths per annum by 2050, antimicrobial resistance is one of the biggest public health threats globally. In recent years, Staphylococcus aureus (S. aureus), the leading cause of skin and soft tissue infections, has become resistant to a number of antibiotics, including methicillin, a β-lactam antibiotic formerly used to treat bacterial infections.

Methicillin-resistant Staphylococcus aureus (MRSA) usually causes skin infections, however, in some cases, it can also lead to lung infections like pneumonia. If left untreated, MRSA can become fatal and cause sepsis. In healthcare settings, MRSA is the culprit for many cases of bloodstream infections as well as surgical site infections. Given its widespread and severe effects, there is an urgent need to develop new antibiotics and formulate alternative strategies to combat resilient pathogens.

While exploring alternative antimicrobial agents, a team of researchers from the University of Hong Kong (HKU), has uncovered the molecular mechanisms behind the antimicrobial properties of silver ions (Ag+), and demonstrated how the multi-targeted mechanism of Ag+ can offer sustainable antimicrobial efficacy and potentially re-sensitise MRSA to antibiotics.

Metal-based compounds have long been used as antimicrobial agents due to their inherent broad-spectrum antimicrobial properties and low chances of resistance. Silver ions and silver nanoparticles, in particular, have been widely used in the healthcare and food industry. However, the molecular mechanisms underlying their antimicrobial effects have largely remained elusive.

In this novel study, Professor Hongzhe Sun, Norman, Cecilia Yip, and colleagues adapted a technological platform, known as LC-GE-ICP-MS, that was previously designed to identify Ag+-binding proteins in S. Aureus , to examine S. aureus. Their investigation led them to discover 38 novel Ag+-binding proteins in S. Aureusat a whole-cell scale. Further bioinformatics analysis and systematic biochemical characterisation revealed that silver ions operate in a “shotgun” mode of action, whereby they target multiple proteins and disrupt various pathways such as glycolysis, oxidative pentose phosphate pathway, and reactive oxygen species stress defence system, all of which induce the death of S. aureus.

However, of the various pathways silver ions target, the team found that the bactericidal effects of Ag+ are primarily hinged upon the disruption of a key enzyme known as 6-phosphogluconate dehydrogenase (6PGDH) in the oxidative pentose phosphate pathway. With the help of X-ray crystallography, the team resolved the first crystal structures of 6PGDH from S. Aureusand observed that Ag+ can interfere with the enzymatic activity of 6PGDH by targeting Histidine 185 in the active site of the enzyme, thus inducing changes in the catalytic pocket that prevent the proper functioning of 6PGDH.

By solving the long-standing question of the molecular targets of silver in S. aureus, their discoveries are expected to validate the benefits of silver-based antimicrobials to enhance the efficacy of conventional antibiotics, laying the groundwork for the development of other metal-based compounds that can re-sensitise resistant pathogens like MRSA to antibiotics and combat antimicrobial resistance. [APBN]

Source: Wang et al. (2021). Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance. Nature communications, 12(1), 1-16.