Nav: Home

Researchers discover new antibiotic effective against drug-resistant bacteria

June 15, 2017



Scientists from Rutgers University-New Brunswick, the biotechnology company NAICONS Srl., and elsewhere have discovered a new antibiotic effective against drug-resistant bacteria: pseudouridimycin. The new antibiotic is produced by a microbe found in a soil sample collected in Italy and was discovered by screening microbes from soil samples. The new antibiotic kills a broad spectrum of drug-sensitive and drug-resistant bacteria in a test tube and cures bacterial infections in mice.

In a paper published in Cell today, the researchers report the discovery and the new antibiotic's mechanism of action.

Pseudouridimycin inhibits bacterial RNA polymerase, the enzyme responsible for bacterial RNA synthesis, through a binding site and mechanism that differ from those of rifampin, a currently used antibacterial drug that inhibits the enzyme. Because pseudouridimycin inhibits through a different binding site and mechanism than rifampin, pseudouridimycin exhibits no cross-resistance with rifampin, functions additively when co-administered by rifampin and, most important, has a spontaneous resistance rate that is just one-tenth the spontaneous resistance rate of rifampin.

Pseudouridimycin functions as a nucleoside-analog inhibitor of bacterial RNA polymerase, meaning that it mimics a nucleoside-triphosphate (NTP), the chemical "building block" that bacterial RNA polymerase uses to synthesize RNA. The new antibiotic binds tightly to the NTP binding site on bacterial RNA polymerase and, by occupying the NTP binding site, prevents NTPs from binding.

Pseudouridimycin is the first nucleoside-analog inhibitor that selectively inhibits bacterial RNA polymerase but not human RNA polymerases.

"Because the NTP binding site of bacterial RNA polymerase has almost exactly the same structure and sequence as the NTP binding sites of human RNA polymerases, most researchers thought it would be impossible for a nucleoside-analog inhibitor to inhibit bacterial RNA polymerase but not human RNA polymerases," said Richard H. Ebright, Board of Governors professor of chemistry and chemical biology and laboratory director at the Waksman Institute of Microbiology at Rutgers-New Brunswick, who led the research.

"But pseudouridimycin contains a side-chain that 'reaches' outside the NTP binding site and 'touches' an adjacent site that is present in bacterial RNA polymerase but not in human RNA polymerases and, as a result, it binds more tightly to bacterial RNA polymerase than to human RNA polymerases," Ebright said.

The fact that pseudouridimycin functions as a nucleoside-analog inhibitor explains the low rate of emergence of resistance to the compound.

"The new antibiotic interacts with essential residues of the NTP binding site that cannot be altered without losing RNA polymerase activity and bacterial viability," Ebright said. "Alterations of the NTP binding site that disrupt binding of the new antibiotic also disrupt RNA polymerase activity, resulting in dead bacteria, rather than resistant bacteria."

"Nucleoside-analog inhibitors that selectively inhibit viral nucleotide polymerases have had transformative impact on the treatment of HIV-AIDS and hepatitis C," said Stefano Donadio, CEO of NAICONS Srl., who co-led the research. "The anti-AIDS drugs Zidovudine, Videx, Zalcitabine, Lamivudine, and Viread are nucleoside-analog inhibitors, and the anti hepatitis-C drugs Solvadi and Harvoni are nucleoside-analog inhibitors."

"Nucleoside-analog inhibitors that selectively inhibit bacterial RNA polymerase could have a similarly transformative impact on the treatment of bacterial infections," Donadio said.

"The discovery also underscores the importance of natural products in providing new antibiotics," he said. "Microbes have had had billions of years to develop 'chemical weapons' to kill other microbes."
-end-
In addition to Ebright and Donadio, the research team included Yu Zhang and David Degen from Rutgers-New Brunswick; Sonia Maffioli, Giancarlo Del Gatto, Stefania Serina, Paolo Monciardini, and Carlo Mazzetti from NAICONS Srl.; Paola Guglierame from NeED Pharma Srl.; Gianpaolo Candiani, Giuseppe Facchetti and Petra Kaltofen from Vicuron Pharmaceuticals Italy Srl.; Thomas Carzaniga and Gianni Dehò from the University of Milan; and Alina Iulia Chiriac and Hans-Georg Sahl from the University of Bonn.

The study was supported by grant R37-GM041376 from the National Institute of General Medical Sciences at the National Institutes of Health, grants R01-AI104660 and U19-AI109713 from the National Institute of Allergy and Infectious Diseases at the NIH, and grants from the Italian Ministry of Research and Regione Lombardia. X-ray diffraction data for the study were collected at beamline F1 of the Cornell High Energy Synchrotron Source, which is supported by the National Science Foundation and the National Institute of General Medical Sciences at the NIH.

Rutgers University

Related Microbes Articles:

Microbes seen controlling action of host's genes
Duke researchers have shown that microbes can control their animal hosts by manipulating the molecular machinery of their cells, triggering patterns of gene expression that consequently contribute to health and disease.
Three-way dance between herbivores, plants and microbes unveiled
What looks like a caterpillar chewing on a leaf or a beetle consuming fruit is likely a three-way battle that benefits most, if not all of the players involved, according to a Penn State entomologist.
Vitamin B12: Power broker to the microbes
In the microbial world, vitamin B12 is a hot commodity.
Gut microbes and bird's breath from the U at #SICB2017
University of Utah researchers will be among the scientists convening in New Orleans for the 2017 Annual Meeting for the Society for Integrative and Comparative Biology Jan.
Gut microbes contribute to recurrent 'yo-yo' obesity
New research in mice may in the future help dieters keep the weight off.
Digital microbes for munching yourself healthy
A research team at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg has taken an important step in modelling the complexity of the human gut's bacterial communities -- the microbiome -- on the computer.
How gut microbes help chemotherapy drugs
Two bacterial species that inhabit the human gut activate immune cells to boost the effectiveness of a commonly prescribed anticancer drug, researchers report Oct.
Soil microbes flourish with reduced tillage
Microbes improve soil quality by cycling nutrients and breaking plant residues down into soil organic matter.
Microbes help plants survive in severe drought
Plants can better tolerate drought and other stressors with the help of natural microbes, University of Washington research has found.
Mix and match microbes to make probiotics last
Scientists have tried to alter the human gut microbiota to improve health by introducing beneficial probiotic bacteria.

Related Microbes Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Changing The World
What does it take to change the world for the better? This hour, TED speakers explore ideas on activism—what motivates it, why it matters, and how each of us can make a difference. Guests include civil rights activist Ruby Sales, labor leader and civil rights activist Dolores Huerta, author Jeremy Heimans, "craftivist" Sarah Corbett, and designer and futurist Angela Oguntala.
Now Playing: Science for the People

#521 The Curious Life of Krill
Krill may be one of the most abundant forms of life on our planet... but it turns out we don't know that much about them. For a create that underpins a massive ocean ecosystem and lives in our oceans in massive numbers, they're surprisingly difficult to study. We sit down and shine some light on these underappreciated crustaceans with Stephen Nicol, Adjunct Professor at the University of Tasmania, Scientific Advisor to the Association of Responsible Krill Harvesting Companies, and author of the book "The Curious Life of Krill: A Conservation Story from the Bottom of the World".