MRSA bacteria use a set of proteins called Helix-Turn-Helix (HTH) factors to both read their DNA and grab hold of messenger RNA molecules—a dual role that researchers have only just discovered. This matters because MRSA is a growing global threat. The bacteria cause life-threatening skin and respiratory infections that are increasingly hard to treat, as they resist both the immune system and multiple antibiotics. MRSA’s survival depends on quickly producing the right proteins at the right time, and HTH proteins were already known to control antibiotic resistance and immune evasion by binding to DNA. The surprise finding that they also bind RNA opens a new front in understanding how MRSA coordinates its attacks. If this research succeeds, it could reveal a fundamental weakness in MRSA’s control system. The team aims to find small molecules that block the RNA-binding activity of specific HTH proteins. In the longer term, these molecules might be developed into drugs that disable MRSA’s ability to resist treatment and evade the immune system—offering a new way to fight infections that current antibiotics cannot touch.
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Antimicrobial medicines have saved millions of lives since the introduction of penicillin in the 1940s. However, their overuse has resulted in the appearance of multidrug-resistant bacteria at a rate that has outpaced the discovery of new antibiotics. The rapid spread of highly virulent and multi-drug-resistant S. aureus strains (such as methicillin-resistant S. aureus (MRSA)) is causing major healthcare problems worldwide as S. aureus skin and respiratory infections can be life-threatening and are becoming increasingly more challenging to treat. MRSA uses several clever tactics to increase its resistance to host immune systems and antibiotic therapies. These include attaching to and killing host cells to extract essential nutrients while evading intracellular immune response and forming biofilm structures that protect the bacterial cells from host immune response and antibiotics. To accomplish this, MRSA must quickly produce new proteins to execute these tasks. Like all organisms, MRSA makes temporary copies of its genes, called messenger RNA (mRNA) molecules. This requires the activity of the transcription machinery, the RNA Polymerase, and other proteins, called transcription factors, that help determine for which genes mRNA copies are generated. The mRNAs can subsequently be read (translated) by another important machinery, called the ribosome, to create proteins. Besides transcription factors, RNA-binding proteins (RBPs) also play vital roles in helping MRSA survive the hostile host environment. By binding to mRNAs, RBPs control how efficiently ribosomes translate the temporary mRNA copies. RBPs can also aid in removing mRNAs that are no longer needed. Although the importance of RBPs for bacteria is well established, we know remarkably little about how these proteins contribute to S. aureus survival during host infection. To address this, we performed pioneering experiments that uncovered many new RBPs in S. aureus. To our surprise, this dataset contained many proteins belonging to a group of transcription factors called Helix-Turn-Helix proteins (HTH). Interestingly, several of these HTH proteins have well-established functions in antibiotic resistance and host immune evasion. Using methodologies from various scientific disciplines, this research programme aims to determine how HTH proteins can recognise distinct DNA and RNA molecules and how important this newly discovered RNA-binding function is for MRSA survival in the host. Finally, using innovative drug discovery techniques, we aim to identify small molecules that control the activity of a select number of HTH proteins. A longer-term goal is to determine whether these small molecules can be repurposed for battling bacterial infections and whether the RNA-binding activities of HTH proteins can be exploited for developing new therapeutics.
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