For decades, doctors have been using antibiotics to fight tuberculosis (TB) (lat. Phthisis). And consistently, the microbe responsible for the disease, Mycobacterium tuberculosis, has been fighting back. When confronted with current drugs, such as the antibiotic rifamycin, the bacterium often mutates in ways that make it resistant to the treatment. Rates of rifamycin resistance are steadily rising, which presents a major problem for doctors attempting to treat TB. But, according to a new study from a team of Rockefeller scientists, nature might have come up with a solution. Rifamycin, or Rif, works by targeting RNA polymerase (RNAP), an enzyme crucial to bacteria’s survival. Resistance develops when the genes coding for RNAP mutate: Even a small genetic change can prevent Rif from binding to the enzyme and obstructing its function. Rifamycin is naturally produced by a bacterium. 

To identify any such analogs, the lab sequenced the genes of microbes found in soil samples collected from locations across the country. They hoped to uncover antibiotics that were genetically related to Rif, but with small variations that allowed them to bind to mutated RNAPs. 

Through their soil probes, the researchers discovered a group of natural antibiotics, known as kanglemycins, or kangs, that share most of their genes with rifamycin. Moreover, analyses revealed that these antibiotics are capable of combatting bacteria that don’t respond to Rif. The team hypothesizes that kangs might have emerged in response to evolutionary pressures that mirror those present in hospitals. In a clinical setting, bacteria react to the antibiotic onslaught by evolving protective mutations. In turn, researchers create more powerful antibiotics; and, over time, bacteria develop further mutations to evade these new attacks. In nature, bacteria and antibiotics may engage in a similar arms race.

Bacteria in dirt compete with one another. And one way for a bacterial species to take out the competition is to produce toxins, like Rif, which act as natural antibiotics. Like bacteria in hospitals, bacteria in soil respond to such threats by mutating in ways that confer resistance to the toxins. To understand what makes these newly discovered antibiotics effective against mutated TB strains, the researchers analyzed their structure. They found that, though their kangs resembled rifamycin, the antibiotics had several distinctive features, including an extra sugar and an extra acid, attached to the core structure. These microscopic flourishes, the researchers learned, endowed the molecule with a new way to bind to and interfere with RNAP, allowing the kangs to target bacteria unaffected by Rif.

The discovery of this docking station supplies researchers with a new strategy for developing yet more powerful antibiotics. Now aware of the hitherto hidden RNAP pocket, scientists can search for, or synthesize, novel drugs that exploit it.