Scientists at McMaster University in Canada have discovered a protein broadly found in bacteria that protects them from antibiotics of the rifamycin family. The findings were published in the journal Molecular Cell in an article titled, “HelR is a helicase-like protein that protects RNA polymerase from rifamycin antibiotics.” The findings underscore that mechanisms of antimicrobial resistance are more complex than realized earlier.
Natural rifamycins and their synthetic derivatives like rifampin and rifabutin constitute a class of antibiotics effective against mycobacterial infections such as tuberculosis, leprosy, and diarrhea. They work by inhibiting bacterial RNA polymerase but do not affect the analogous mammalian enzyme. DNA-directed RNA polymerases are enzymes that synthesize RNA from a DNA template and are therefore essential for survival.
Mutations in bacterial RNA polymerases are the predominant cause of bacterial resistance against rifamycins, but many bacteria encode specific enzymes that catalyze sophisticated mechanisms to change and block rifamycins. The expression of these specific enzymes is controlled by a palindromic sequence in the bacterial genome, 19 base pairs long, called RAE (rifamycin-associated element).
Using the presence of RAE sequences as a guide, the authors in this study identified a helicase-like protein called HelR in the bacteria Streptomyces venezuelae that renders bacteria resistant to rifamycins. The resistant bacteria use HelR to “kick off” the antibiotic from RNA polymerase. Once the rifamycin is dislodged, the bacteria use specially adapted proteins to attack and destroy it.
“What we’ve discovered is a brand-new trick up the sleeves of bacteria to evade this class of antibiotics,” said Gerry Wright, PhD, who leads the McMaster-based Global Nexus for Pandemics and Biological Threats and is the senior author of the paper. “It’s like a one-two punch. It’s fascinating and it’s so crafty.”
Wright and his colleagues are combing their database to identify other bacteria that use similar ploys to survive rifamycin attacks and potential vulnerabilities in these bacteria that can be exploited to create urgently needed new rifamycin antibiotics.
“We find the genes associated with this resistance are widespread in environmental bacteria and some human pathogens—luckily not the ones that cause tuberculosis, but some related ones,” said Wright.
HelRs are broadly found in the bacterial phylum Actinobacteria which consists of mostly Gram-positive bacteria and includes several Mycobacterial pathogens. This poses another challenge in developing effective rifamycin derivatives.
“Every time we think we’ve figured out all the ways bacteria resist antibiotics, along comes something like this, to let us know there are tricks we hadn’t even thought of before,” said Wright.
Wright urges governments, universities, and manufacturers to collaborate to develop new and effective antibiotics and to counter the reluctance of most pharmaceutical companies to invest in their discovery and development on account of low returns on investment compared to drugs prescribed long-term.
“Antimicrobial resistance is a huge and growing global health concern that should be commanding much more attention and far more research resources,” said Wright. “We have to keep reminding people just how tricky these bugs are. We’ve all been focused on COVID these past two and half years, but antimicrobial resistance continues to bubble under the radar and these bacteria have continued to innovate and diversify their mechanisms of resistance. We have to keep working to make sure we really do understand the enemy.”
Wright says the diversity of mechanisms that bacteria can use to evade antibiotics continues to amaze. He cautions that we ignore this diversity at our peril and mentions the need for efforts like One Health to better understand this environmental reservoir of resistance. McMaster is playing a major role in studying antimicrobial resistance and developing solutions, he said.