New antibiotic fertilizer clears multidrug-resistant gonorrhea infection in mice in a single oral dose, according to a new study led by researchers at Penn State University and Emory University. The fertilizer targets a molecular pathway found in bacteria but not humans and may lead to new treatments for gonorrhea and other bacterial infections, such as tuberculosis and MRSA.
The research team, which also includes scientists from biopharmaceutical company Microbiotix, University of Apparel Services, and Florida State, published their findings in a paper published March 19 in the journal Nature Communication.
Gonorrhea affects more than 500 thousand people in the United States each year, and several strains of the disease-causing bacteria, Neisseria gonorrhoeae, are resistant to a number of widely used antibiotics. today. For this reason, the Centers for Disease Control and Prevention (CDC) lists multidrug gonorrhea as one of the top five most serious emergency threats today.
Many conventional antibiotics focus on a translational process – when proteins are made based on information in a genetic material – within the bacteria. Over the past decade, we have been studying a family of compounds that instead block the translation pathway in bacteria, which bacteria use to make mistakes. specific resolution during protein synthesis. In this paper, we present the hypothesis that inhibition of the pathway can effectively translate multidrug-resistant gonorrhea in animals. “
Ken Keiler, professor of biochemistry and molecular biology at Penn State and author of the paper
The previous researchers identified a promising intermediate inhibitor that clears gonorrhea infection in laboratory cultures but is ineffective in animals because the fertilizer breaks down. In this study, members of the research team at Microbiotix strategically modified the strategy to determine which parts of the structure were necessary to block the path and could be modified to adapt it. improve sustainability.
“Our flight repetition campaign evaluated more than 500 versions of the fertilizer to evaluate their strength, toxicity, and other medicinal properties,” said Zachary Aron, director of chemistry at Microbiotix and author of the paper. “We concluded that the center of the cement area plays a critical role in inhibiting the translation pathway, but changes at the periphery may alter its pharmacological properties. By modifying an action group to reduce the main mode of metabolism, we will be able to produce versions of the substance that are much more stable in animals. “
Members of the research team at the University of Uniformed Services then tested one of these modified fertilizers, MBX-4132, in mice. Their tests used the WHO-X gonorrhea strain, an extremely potent pathogen that is resistant to almost all approved antibiotics. One oral dose of the fertilizer completely eliminated the infection in 80% of mice within six days, and the bacterial load in the remaining 20% was significantly reduced.
“Developing a single-dose treatment for gonorrhea is extremely important,” Keiler said. “In some cases, bacteria can improve drug resistance when jumping to extra doses, for example when a patient begins to feel better and stops taking antibiotics. With a single dose therapy, a patient could complete the treatment at the time of visiting their health care provider. “
To better determine how the fertilizer impedes the translation pathway, members of the research team at Emory University and Florida State University used a cryo-electron microscope (cryo-EM) to produce high-resolution images of the fertilizer. make the cement while attaching to the barrier. ribosome – the macromolecule where proteins are synthesized.
“A derivative of MBX-4132 binds to a place on the ribosome that is different from all known antibiotic binding sites,” said Christine Dunham, associate professor of biochemistry at Emory University and author of the paper . “The new drug also clears an area of ribosomal protein that we think may be important during the normal process of translation. Since translation occurs only in bacteria and not in humans, we hope that the appearance of the fertilizer affects protein synthesis in humans is greatly reduced, an hypothesis that is strongly supported by the safety and selectivity studies conducted Microbiotix. “
The research team plans to optimize the fertilizer before proceeding with preclinical experiments.
“This type of fertilizer is definitely a broad-spectrum protector,” Keiler said. “It is effective against most Gram-positive bacteria – including tuberculosis and difficult-to-treat staph infections (MRSA) – and some Gram-negative bacteria and may be a promising candidate for future treatments.In this study, we will set the groundwork for the use of this type of fertilizer and demonstrate that obstruction is in the way. translation in bacteria is the operational antibiotic strategy. “
Aron, ZD, et al. (2021) Translational inhibitors attach to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo. Nature Communication. doi.org/10.1038/s41467-021-22012-7.