Researchers from Hong Kong University of Science and Technology (HKUST) has unlocked the inner workings of RNA polymerase-inhibiting Myxopyronin antibiotics, opening doors to the development of a new class of drugs targeting a sub-component in RNA-polymerase, the β-lobe.
As globalised citizens of the 21st century, we are no stranger to the looming threat of antibiotic resistance (ABR). Dubbed as one of the greatest hazards to global health, food security and development, this phenomenon is accelerating at a dangerously fast pace in all parts of the world. In fact, ABR is forecasted to become the leading cause of death accounting for 10 million deaths per annum by 2050.
In technical terms, ABR refers to the inherent or acquired ability of microorganisms to survive and grow in the presence of antibiotics, which should otherwise effectively inhibit their growth or kill given microorganisms. The sharp increase in the prevalence of ABR has been aggravated by globalisation and continued misuse use of antibiotics, thus rendering many antibiotics ineffective. The gravity of this global health threat calls for an equally large-scale collective collaboration and innovation of new antibacterial drugs.
Responding to this call is a team of researchers from Hong Kong University of Science and Technology (HKUST) that has recently uncovered the mechanics of Myxopyronin, an antibiotic that inhibits RNA polymerase (RNApol) activity, and brought to light a new target for antibiotics development.
RNApol facilitates an essential process called DNA melting, whereby the double-stranded DNA is loaded and separated in the loading gate of RNApol with the help of a claw-like “pincers”. Working together, these flexible pincers, composed of the “clamp” and “β-lobe”, help to open and close the loading gate of RNApol in order to initiate or terminate transcription. Transcription is the process of copying genetic information from DNA to messenger RNA (mRNA), which acts as a template for translation of proteins to carry out cellular functions. The team has found that inhibiting RNA polymerase by targeting the “clamp” or “β-lobe” can effectively disrupt transcription, protein production and so kill bacteria.
With the aid of the newly-developed quasi-Markov State Model (qMSM), the research team examined the process of DNA melting and found that Myxopyronin is capable of binding to a partially closed form of the “clamp”, thus preventing the clamp from closing, inhibiting the DNA melting process and successfully killing the bacteria. Their study sheds light to the precise mechanism by which antibiotics influence the flexibility and shape of specific components of RNApol.
To add, they also made an unprecedented discovery of the role of β-lobe in DNA loading which can independently load the DNA without opening the clamp. This finding suggests that disrupting the β-lobe may be sufficient to inhibit the entire transcription process, and pave the way for the development of new antibiotics that specifically target the β-lobe of RNApol.
Professor Huang, who spearheaded the study from the Department of Chemistry and Department of Chemical and Biological Engineering at HKUST, elaborated on their findings, “The shape of bacterial RNA polymerase resembles a crab claw that works like a pincer. The shape and flexibility of the two pincers are important for RNA Polymerase to hold and separate the double-helix form of DNA into single-stranded. We showed that an antibiotic that targets the movement of the pincers would be a promising as a drug candidate. What is more exciting, is that we also discovered a novel critical role of the β-lobe that can serve as a new target for future antibiotics development."