Researchers have discovered a significant and previously unknown mechanism that many bacteria use to resist antibiotics.

Using a combination of computation and physical observation in the laboratory, the researchers have unraveled a sophisticated process that some commonly occurring bacteria use to save themselves from the rifamycin class of antibiotics, which occur naturally and are also manufactured to treat infectious diseases.

Rifamycins work by binding to RNA polymerase, a protein essential for bacterial life.

The resistant bacteria, which occur widely in the environment and in some human pathogens, have developed a protein that can eject the antibiotic from RNA polymerase. Once the rifamycin is dislodged, they use specially adapted proteins to attack and destroy it.

The researchers identify a helicase-like protein, HelR, in Streptomyces venezuelae that confers broad-spectrum rifamycin resistance. They show that HelR also promotes tolerance to rifamycins, enabling bacterial evasion of the toxic properties of these antibiotics. HelR forms a complex with RNAP and rescues transcription inhibition by displacing rifamycins from RNAP, thereby providing resistance by target protection .

“What we’ve discovered is a brand-new trick up the sleeves of bacteria to evade this class of antibiotics,” explains the researcher. “It’s like a one-two punch. It’s fascinating and it’s so crafty.”

The discovery shows that the mechanisms of antimicrobial resistance (AMR) are more complex and highly evolved than scientists had previously recognized.
HelRs are broadly distributed in Actinobacteria, including several opportunistic Mycobacterial pathogens, offering yet another challenge for developing new rifamycin antibiotics.

Now the researchers are combing their database of tens of thousands of samples to see if other bacteria use parallel processes and whether they reveal vulnerabilities that can be exploited to create urgently needed new antibiotics.

Their work is described in a paper published in the influential journal Molecular Cell.

The author says the discovery gives him with new respect for nature’s adaptability and renews his enthusiasm for finding and exposing other methods bacteria use to ensure their survival.

“We’ve been facing this AMR problem for many years,” the author says. “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.”

AMR is a huge and growing global health concern that should be commanding much more attention and far more research resources, the author says.

Though the effectiveness of penicillin, rifamycin and other established antibiotic treatments is waning quickly, most pharmaceutical companies are not actively developing new antibiotics, the author says and explains that drug discovery and development is tremendously expensive, and the financial return on investment in antibiotics would be low since they don’t generate as much revenue as prescription medications that patients use for years at a time.

https://www.cell.com/molecular-cell/fulltext/S1097-2765(22)00602-5