Fighting deadly disease, one molecule at a time

Researchers from the University of Minnesota College of Veterinary Medicine (CVM) and the College of Science and Engineering (CSE) have discovered a promising new target against methicillin-resistant Staphylococcus aureus (MRSA), a bacteria that can cause fatal infections that are increasingly difficult to treat with existing antibiotics.

Antimicrobial resistance—when microbes such as bacteria adapt over time to resist medicines and render treatment ineffective—is a top global public health threat, according to the World Health Organization. MRSA may well be the exemplar of that threat, causing more deaths in the US than any other drug-resistant pathogen. MRSA infections are common in healthcare facilities where they can cause serious problems for patients, but as instances of community spread beyond healthcare facilities become more frequent, it has become even more crucial to discover alternative treatments.

To circumvent the resistance that some bacteria develop against antibiotics that are designed to kill them, one alternative approach is to instead control their virulence, or their ability to spread infection.

Bacteria have complex networks that regulate their virulence in response to environmental stimuli, including temperature, nutrients, pH changes, and even antibiotic exposure. In this study, the researchers, led by Yinduo Ji from CVM and Erin Carlson from CSE, focused on inhibiting one key component of that network: an enzyme known as histidine kinase (HK). HKs work like sensors to detect stimuli in the environment and signal the bacteria to respond accordingly. By blocking the response of HK, the researchers hypothesized, they could essentially jam the system that enables the bacteria to spread and cause disease.

They built on previous work where they had taken a similar approach to identify molecules that reduce the virulence of another dangerous infection-causing bacteria called Pseudomonas aeruginosa. Here, the same strategy was used successfully to identify a class of compounds with a specific molecular structure called PMI-5 that targets HKs and can reduce the virulence of MRSA.

While further studies are needed to fully understand how PMI-5 interacts with MRSA bacteria, the researchers anticipate that the compounds they have identified could be used together with currently utilized antibiotics or as a stand-alone therapy, augmenting the immune system response to fight infections. And since the compounds do not kill bacteria but instead act as anti-virulence agents, they have the potential to control the disease without exacerbating antibiotic resistance—making them a crucial new tool in the public health toolbox.

Read the full study in Chemical Science.