MAR 21, 2021 7:58 AM PDT

Potent Drug Rapidly Clears Drug-Resistant Gonorrhea in Mouse Model

WRITTEN BY: Carmen Leitch

A mouse model has shown that it's possible to clear a multi-drug resistant gonorrhea infection with only one dose of antibiotic. This antibiotic targets a biochemical pathway in bacteria. That may be great news for those with drug-resistant gonorrhea (the incidence of which is rising), and it may also help scientists that are looking for treatments for other drug-resistant microbes like MRSA (Methicillin-resistant Staphylococcus aureus). This work has been reported in Nature Communications.

A medical illustration of drug-resistant Neisseria gonorrhoeae bacteria / Credit: CDC/ Antibiotic Resistance Coordination and Strategy Unit / Medical Illustrator: Alissa Eckert

Every year in the Unites States, over 500,000 people are diagnosed with gonorrhea, which is caused by several strains of pathogenic bacteria called Neisseria gonorrhoeae. The germ is considered to be among the country's most dangerous public health threats.

"Many current antibiotics target the process of translation - when proteins are made based on information in genetic material - within the bacteria," said study co-author Ken Keiler, professor of biochemistry and molecular biology at Penn State. "Over the last decade, we have been investigating a family of compounds that instead inhibit the trans-translation pathway in bacteria, which bacteria use to fix certain kinds of errors during protein synthesis. In this paper, we provide a proof-of-concept that inhibiting the trans-translation pathway can effectively clear multi-drug resistant gonorrhea in animals."

Previous work found a compound that could eliminate a gonorrhea infection, but it broke down and as such, was ineffective. In this work, the research team, which included scientists from Penn State, Emory University, Microbiotix, the Uniformed Services University, and Florida State, altered the compound to find the parts that were required, and where stability could be improved.

MBX-4132, binds to the bacterial ribosome and, in so doing, displaces a region of a protein (bL27, purple) that is critical to the trans-translation pathway in bacteria. / Credit: Dunham Lab, Emory University

"Our iterative optimization campaign evaluated over 500 versions of the compound to assess their potency, toxicity, and other pharmacological properties," said study co-author Zachary Aron, director of chemistry at Microbiotix.

One new compound called MBX-4132 was tested in mice against an extremely virulent strain that resists most antibiotics. It only took one dose of the MBX-4132 to totally eliminate the infection in 80 percent of mice in six days. The level of bacteria went down dramatically in the other 20 percent.

"Developing a single dose therapy for gonorrhea is incredibly important," said Keiler. "In some cases, bacteria can develop resistance to a drug when additional doses are skipped, for example when a patient starts to feel better and stops taking antibiotics. With a single dose therapy, a patient could complete the treatment during a visit to their health provider."

In this study, the researchers also used cryo-electron microscopy to learn more about how MBX-4132 attaches to the ribosome (which makes the proteins) in the bacterial cells. They found that the compound attaches to the ribosome in a different location than other known antibiotics that act in this way, and can displace a ribosomal protein.

"This type of compound is actually a broad-spectrum inhibitor," said Keiler. "It is effective against most Gram-positive bacteria including tuberculosis and difficult-to-treat staph infections (MRSA) and some Gram-negative bacteria and could be a promising candidate for future treatments. In this study, we lay the groundwork for using this type of compound and demonstrate that inhibiting the trans-translation pathway in bacteria is a viable antibiotic strategy."

The scientists are planning to optimize the compound further before they plan preclinical trials.

Sources: AAAS/Eurekalert! via Penn State, Nature Communications

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