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For decades, doctors have been using antibiotics to fight tuberculosis. And systematically, the microbe responsible for the disease, Mycobacterium tuberculosis fought back. When faced with current medications, such as the antibiotic rifamycin, the bacterium often undergoes a mutation that makes it resistant to treatment.
Rifamycin resistance rates are steadily increasing, posing a major problem for physicians attempting to treat tuberculosis. But, according to a new study by a team of Rockefeller scientists, nature could have come up with a solution. The study, published in Nature Communications suggests that an antibiotic present in the dirt can destroy mutant mycobacteria.
Antibiotics of Nature
Rifamycin, or Rif, works by targeting the enzyme RNA polymerase (RNAP). crucial for the survival of bacteria. Resistance develops when genes encoding RNAP mutate: even a small genetic change can prevent the RIF from binding to the enzyme and hindering its function.
To get around the resistance, the researchers needed a drug that acted like Rif, but that could bind to RNAP. , even in the presence of mutations. And while some scientists might turn to the lab to synthesize such a molecule, Sean F. Brady, a professor at Evnin, has turned to the environment.
"Rifamycin is naturally produced by a bacterium," he says. "So I wanted to know if nature had also made Rif badogs, rifamycin-like molecules with slight differences."
To identify such badogues, Brady's laboratory sequenced the genes for microbes found in soil samples taken from locations across the country. They hoped to discover antibiotics genetically related to Rif, but with small variations that allowed them to bind to mutated RNAP.
That's exactly what they found.
Through their soil probes, researchers discovered a group of natural antibiotics. , known as kanglemycines, or kangs, who share most of their genes with rifamycin. In addition, badyzes by James Peek, a postdoctoral badociate, revealed that these antibiotics are able to fight bacteria that do not respond to Rif.
Brady hypothesizes that kangs may have emerged in response to evolutionary pressures similar to those present in hospitals. In clinical settings, bacteria react to the attack of antibiotics by developing protective mutations. In turn, researchers create more potent antibiotics. and, over time, bacteria develop new mutations to escape these new attacks. In nature, according to Brady, bacteria and antibiotics can engage in a similar arms race.
Bacteria present in the earth compete with each other. And one way for a bacterial species to break free from competition is to produce toxins, such as Rif, that act as natural antibiotics. Like bacteria in hospitals, soil bacteria respond to these threats by mutating to confer resistance to toxins. But, over time, their rival bacteria could also mutate, producing even more potent antibiotics. Kangs, Brady speculates, could be the result of this type of competition.
"Natural antibiotics may experience the same selective pressure that we apply to the clinic," he says. "And if it did, we would see rifamycin-like badogs, like kangs, that overcome resistance."
A Polymerase-Friendly Pocket
To understand what makes these recently discovered antibiotics effective against mutated strains of tuberculosis, Elizabeth Campbell, an badociate research professor, Seth A. Darst, Professor Jack Fishman, and Principal Research Associate, Mirjana Lilic, badyzed their structure. They found that although their kangs resemble rifamycin, antibiotics had several distinguishing features, including additional sugar and additional acid, related to the central structure. The researchers learned that these microscopic flourishes provided the molecule with a new way to bind to and interfere with RNAP, allowing kangs to target non-Rif-affected bacteria.
"We found that the extra sugar allowed the kanglemycin from a pocket RNAP that the other drugs did not benefit from," says Campbell. In fact, before this study, scientists were not aware of the existence of such a pocket.
The discovery of this docking station provides researchers with a new strategy for developing even more potent antibiotics. Now aware of the pocket of RNAP, hitherto hidden, scientists can search for or synthesize new drugs that exploit it.
"We would always like to see an increase in potency and a broader activity against resistant insects," said Campbell. "But this study tells us that we are on the right track."
More information:
James Peek et al., Kanglemycines, rifamycin congeners, are active against rifampicin-resistant bacteria via a separate mechanism, Nature Communications (2018). DOI: 10.1038 / s41467-018-06587-2
For decades, doctors have been using antibiotics to fight tuberculosis. And systematically, the microbe responsible for the disease, Mycobacterium tuberculosis fought back. When faced with current medications, such as the antibiotic rifamycin, the bacterium often undergoes a mutation that makes it resistant to treatment.
Rifamycin resistance rates are steadily increasing, posing a major problem for physicians attempting to treat tuberculosis. But, according to a new study by a team of Rockefeller scientists, nature could have come up with a solution. The study, published in Nature Communications suggests that an antibiotic found in dirt can destroy mutant mycobacteria.
Antibiotics of Nature
Rifamycin, or Rif, works by targeting RNA polymerase. (RNAP), an enzyme crucial for the survival of bacteria. Resistance develops when genes encoding RNAP mutate: even a small genetic change can prevent the RIF from binding to the enzyme and hindering its function.
To get around the resistance, the researchers needed a drug that acted like Rif, but that could bind to RNAP. , even in the presence of mutations. And while some scientists might turn to the lab to synthesize such a molecule, Sean F. Brady, a professor at Evnin, has turned to the environment.
"Rifamycin is naturally produced by a bacterium," he explains. "So I wanted to know if nature had also made Rif badogues, rifamycin-like molecules with slight differences."
To identify such badogues, Brady's laboratory sequenced the genes for microbes found in soil samples locations across the country. They hoped to discover antibiotics genetically related to Rif, but with small variations allowing them to bind to mutated RNAP.
That's exactly what they found.
Through their soil probes, researchers discovered a group of natural antibiotics. , known as kanglemycines, or kangs, who share most of their genes with rifamycin. In addition, badyzes by James Peek, a postdoctoral badociate, revealed that these antibiotics are able to fight bacteria that do not respond to Rif.
Brady hypothesizes that kangs may have emerged in response to evolutionary pressures similar to those present in hospitals. In clinical settings, bacteria react to the attack of antibiotics by developing protective mutations. In turn, researchers create more potent antibiotics. and, over time, bacteria develop new mutations to escape these new attacks. In nature, according to Brady, bacteria and antibiotics can participate in a similar arms race.
Bacteria present in the earth compete with each other. And one way for a bacterial species to break free from competition is to produce toxins, such as Rif, that act as natural antibiotics. Like bacteria in hospitals, soil bacteria respond to these threats by mutating to confer resistance to toxins. But, over time, their rival bacteria could also mutate, producing even more potent antibiotics. Kangs, Brady speculates, could be the result of this type of competition.
"Natural antibiotics may be under the same selective pressure that we apply to the clinic," he says. "And if it did, we would see rifamycin-like badogs, like kangs, that overcome resistance."
A Polymerase Friendly Pocket
Understanding what makes these recently discovered antibiotics effective against Elizabeth Campbell, Associate Research Professor, Seth A. Darst, Professor Jack Fishman, and Associate Professor main research, Mirjana Lilic, badyzed their structure. They found that although their kangs resemble rifamycin, antibiotics had several distinguishing features, including additional sugar and additional acid, related to the central structure. The researchers learned that these microscopic flourishes provided the molecule with a new way to bind and interfere with RNAP, allowing kangs to target non-Rif-affected bacteria.
"We found that the extra sugar allowed the kanglemycin from an RNAP pocket that other drugs did not benefit from," says Campbell. In fact, before this study, scientists were not aware of the existence of such a pocket.
The discovery of this docking station provides researchers with a new strategy for developing even more potent antibiotics. Now aware of the hitherto hidden RNAP pocket, scientists can research or synthesize new drugs that exploit it.
"We would always like to see an increase in potency and a broader activity against resistant insects," said Campbell. "But this study tells us that we are on the right track."
More information:
James Peek et al., Kanglemycins, rifamycin congeners, are active against rifampicin-resistant bacteria via a separate mechanism, Nature Communications (2018). DOI: 10.1038 / s41467-018-06587-2
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