New antibiotic compounds can effectively eliminate multidrug-resistant gonorrhea in animals

A new antibiotic compound eliminates the infection of multidrug-resistant gonorrhea in mice with a single oral dose, according to a new study led by researchers at Penn State University and Emory University. The compound targets molecular pathways found in bacteria but not in humans, and may lead to new treatments for infections from other bacteria such as gonorrhea, tuberculosis and MRSA.

A research team, including scientists from biopharmacy companies Microbiotix, Uniformed Services University, and Florida State, published their results in a treatise published in a journal on March 19. Nature Communications..

Gonorrhea infects more than 500,000 people each year in the United States, and gonorrhea, some strains of the bacterium that causes the disease, is resistant to the antibiotics used today. For this reason, the US Centers for Disease Control and Prevention (CDC) lists multidrug-resistant gonorrhea as one of the five most dangerous and urgent threats today.

Many of today’s antibiotics target the translation process in bacteria (when proteins are made based on genetic information). For the past decade, we have been investigating a family of compounds that block the bacterial translation pathway. Bacteria are used to correct certain types of errors during protein synthesis. This paper provides a proof of concept that blocking the translation pathway can effectively eliminate multidrug-resistant gonorrhea in animals. “

Ken Kyler, a professor of biochemistry and molecular biology at Pennsylvania State University and author of the treatise

Researchers have previously identified promising translation inhibitors that remove gonorrhea infections in laboratory cultures, but they have no effect in animals because the compounds break down. In this study, members of the Microbiotix research team strategically modify compounds to identify which parts of the structure are needed to block pathways and which parts can be changed to improve stability. Did.

“Our iterative optimization campaign evaluated more than 500 versions of the compound to evaluate its efficacy, toxicity, and other pharmacological properties,” said Microbiotix’s chemistry director and author of the paper. Zachary Aron says. “We have determined that the central region of the compound plays an important role in blocking the translational pathway, but the peripheral modifications can be modified to regulate its pharmacological properties. The functional groups can be modified for metabolism. By bypassing the main mechanism of, we can create a much more stable version of the compound in animals. “

Next, members of the Uniformed Services University research team tested one of these modified compounds, MBX-4132, in mice. Their experiments utilized the gonorrhea strain WHO-X, a highly toxic pathogen resistant to almost all approved antibiotics. A single oral dose of the compound completely eliminated 80% of mouse infections within 6 days and dramatically reduced the bacterial load of the remaining 20%.

“Developing a single-dose therapy for gonorrhea is very important,” Keiller said. “In some cases, skipping additional doses, such as when the patient feels better and stops taking antibiotics, can cause the bacteria to develop drug resistance. With single-dose therapy, the patient visits health. You can complete the treatment during the provider. “

To more accurately determine how a compound interferes with the translation pathway, members of the Emory University and Florida State University research teams used a cryo-electron microscope (cryo-EM) to turn the compound into bacteria. I created a high resolution image when combining. Ribosome-A macromolecule from which proteins are synthesized.

“Derivatives of MBX-4132 bind to ribosome positions that differ from all known antibiotic binding sites,” said Christine Dunham, an associate professor of biochemistry at Emory University and author of the treatise. .. “The new drug also replaces regions of the ribosomal protein that appear to be important in the normal translation process. Translations occur only in bacteria and not in humans, so compounds can affect proteins. Hopefully, human synthesis is significantly reduced. This hypothesis is strongly supported by safety and selectivity studies conducted by Microbiotix. “

The research team plans to further optimize the compound before conducting preclinical trials.

“This type of compound is actually a broad spectrum inhibitor,” says Keyer. “It is effective against most Gram-positive and some Gram-negative bacteria, including tuberculosis and difficult-to-treat staphylococcal infections (MRSA), and may be a promising candidate for future treatment. Studies have laid the groundwork for the use of this type of compound and show that blocking bacterial transtranslation pathways is a viable antibiotic strategy. “