[ad_1]
For decades, doctors have been using antibiotics to fight tuberculosis. And systematically, the microbe responsible for the disease, Mycobacterium tuberculosis, is beaten. 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 trying 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 dust can destroy mutant mycobacteria.
Antibiotics of nature
Rifamycin, or Rif, works by targeting RNA polymerase (RNAP), an enzyme essential for bacterial survival. 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 circumvent the resistance, the researchers needed a drug that acts like Rif, but can 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 analogues, molecules that look like rifamycin, but have slight differences."
To identify such analogues, Brady's laboratory sequenced the genes for microbes found in soil samples collected across the country. They hoped to discover antibiotics genetically related to Rif, but with small variations that would allow them to bind to mutated RNAP.
That's exactly what they found.
With the help of their soil probes, the researchers discovered a group of natural antibiotics, called kanglemycines, or kangs, that share most of their genes with rifamycin. In addition, analyzes by postdoctoral associate James Peek revealed that these antibiotics are able to fight bacteria that do not respond to the Rif virus.
Brady hypothesizes that kangs may have emerged in response to evolving pressures that mirror 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 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.
"It's possible for natural antibiotics to experience the same selective pressure that we apply to the clinic," he says. "And if that were the case, we would see natural analogs to rifamycin, like kangs, that overcome resistance."
A suitable polymerase pocket
To understand what makes these recently discovered antibiotics effective against mutated strains of tuberculosis, Elizabeth Campbell, Associate Professor of Research, Seth A. Darst, Professor Jack Fishman and Associate Researcher Mirjana Lilic have analyzed 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 to anchor in a pocket of RNAP that other drugs had not benefited from," says Campbell. In fact, she says, before this study, scientists were unaware 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. Conscious of the RNAP pocket, hitherto hidden, scientists can research or synthesize new drugs that exploit it.
"We would always like to see increased potency and broader activity against resistant insects," Campbell said. "But this study tells us that we are on the right track."
More information:
James Peek et al., Congenese kanglemycins of rifamycin 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, is beaten. 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 trying 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 dust can destroy mutant mycobacteria.
Antibiotics of nature
Rifamycin, or Rif, works by targeting RNA polymerase (RNAP), an enzyme essential for bacterial survival. 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 circumvent the resistance, the researchers needed a drug that acts like Rif, but can 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 analogues, molecules that look like rifamycin, but have slight differences."
To identify such analogues, Brady's laboratory sequenced the genes for microbes found in soil samples collected across the country. They hoped to discover antibiotics genetically related to Rif, but with small variations that would allow them to bind to mutated RNAP.
That's exactly what they found.
With the help of their soil probes, the researchers discovered a group of natural antibiotics, called kanglemycines, or kangs, that share most of their genes with rifamycin. In addition, analyzes by postdoctoral associate James Peek revealed that these antibiotics are able to fight bacteria that do not respond to the Rif virus.
Brady hypothesizes that kangs may have emerged in response to evolving pressures that mirror 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 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.
"It's possible for natural antibiotics to experience the same selective pressure that we apply to the clinic," he says. "And if that were the case, we would see natural analogs to rifamycin, like kangs, that overcome resistance."
A suitable polymerase pocket
To understand what makes these recently discovered antibiotics effective against mutated strains of tuberculosis, Elizabeth Campbell, Associate Professor of Research, Seth A. Darst, Professor Jack Fishman and Associate Researcher Mirjana Lilic have analyzed 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 to anchor in a pocket of RNAP that other drugs had not benefited from," says Campbell. In fact, she says, before this study, scientists were unaware 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. Conscious of the RNAP pocket, hitherto hidden, scientists can research or synthesize new drugs that exploit it.
"We would always like to see increased potency and broader activity against resistant insects," Campbell said. "But this study tells us that we are on the right track."
More information:
James Peek et al., Congenese kanglemycins of rifamycin are active against rifampicin-resistant bacteria via a separate mechanism, Nature Communications (2018). DOI: 10.1038 / s41467-018-06587-2
Source link
