A new antibiotic to treat gonorrhea

Gonorrhea is a sexually transmitted infection (STI) caused by the bacterium Neisseria gonorrhoeae. This infection is commonly transmitted through sexual contact with an infected person, including vaginal, anal, and oral sex. Gonorrhea is one of the most common STIs with nearly 100 million people worldwide contracting it each year.

If left untreated, gonorrhea can lead to serious health problems. In women, it can cause pelvic inflammatory disease (PID), which can lead to infertility and chronic pelvic pain. In men, it can cause a painful condition called epididymitis (inflammation of the epididymis). The epididymis serves as a link between the testicle and the vas deferens whose role is to carry sperm to the urethra.

Approximately half of individuals with gonorrhea exhibit no symptoms. However, for those who do, the infection can result in discomfort in the joints and a burning sensation during urination. Symptoms commonly involve the genital area.

Diagnosis is made by a PCR test for N. gonorrhoeae DNA from bodily fluids such as urine.

Fortunately, gonorrhea can be effectively treated with antibiotics with symptoms inproving "within a few days" (NHS). The treatment involves a single injection usually in the buttocks or thigh.

The three main antibiotics against gonorrhea are the following:

• Ceftriaxone: This is a third-generation cephalosporin antibiotic. It works by interfering with the synthesis of the bacterial cell wall. Ceftriaxone binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall.
• Azithromycin: This is a macrolide antibiotic. It works by binding to the 50S ribosomal subunit of the bacteria, thereby inhibiting bacterial protein synthesis.
• Doxycycline: This is a tetracycline antibiotic and it functions similarly to Azithromycin by inhibiting protein synthesis. It binds to the 30S ribosomal subunit of the bacteria, preventing the attachment of aminoacyl-tRNA to the mRNA-ribosome complex.

The increase in antibiotic-resistant varieties of Neisseria gonorrhoeae has made it necessary to use combination therapy for effective treatment. The most potent approach involves administering a ceftriaxone injection alongside an azithromycin pill.

Thus, there has been much anticipation for the clinical trial of a new antibiotic zoliflodacin, which is the first to be developed in decades against gonorrhea. The results were positive with patients receiving zoliflodacin (as a pill) showing the same benefit (i.e. curing infection) as those in the control group receiving the standard of care combination of ceftriaxone and azithromycin. The study additionally demonstrated that the medication was safe, and well-tolerated by the subjects (Nature News).

Another attractive feature of zoliflodacin is that its mechanism of action is distinct from other commonly used antibiotics. It works by inhibiting the bacterial DNA gyrase and topoisomerase IV enzymes. These enzymes are critical for bacterial DNA replication, transcription, and repair. Thus, bacteria resistant to the current group of antibiotics in use are very unlikely to be also resistant to zoliflodacin.

Although not yet approved by the FDA, zoliflodacin will be a powerful new weapon in the battle against gonorrhea once it is approved which should happen in the near future.

A second aspect to the story more broadly concerns the development of new antibiotics against a host of bacterial pathogens, not just gonorrhea. As more and more bacteria become resistant to the current generation of antibiotics there is concern that a "superbug" may evolve that is resistant to all of these antibiotics. Such a catastrophic situation would be avoided if there is a steady stream of new antibiotics in the pipeline to supplement the existing ones; but there isn't. Most pharmaceutical companies have ceased developing antibiotics due to lack of profitability. The cost of putting a new drug through clinical trials is enormous, and the returns at least in the beginning would be meager because the existing antibiotics are cheap and effective (for the time being).

To fill this gap, The Global Antibiotic Research and Development Partnership (GARDP) was created as a non-profit organization focused on the research and development of new antibiotic treatments (NYTimes). The organization is funded by a number of countries and health organizations including the European Union. One of their first major projects was the development of zoliflodacin. In a collaboration with the biotechnology company Innoviva Specialty Therapeutics, GARDP funded the Phase 3 trial of zoliflodacin (the largest and most expensive of the three trials needed for approval by the FDA), and in return obtained the rights to distribute the drug in approximately 160 less economically advanced nations, while Innoviva kept the rights to market it in wealthier countries. 

This type of public-private partnership can serve as a template for the future development of other antibiotics and perhaps other drugs that may have limited commercial appeal to pharmaceutical companies.

Figure 1. The chemical structure of zoliflodacin. It was first identified in a chemical screen for antibiotics by Pharmacia & Upjohn. The structure was further refined by AstraZeneca and then Entasis Pharmaceuticals, which is a subsidiary of Innoviva Specialty Therapeutics (Wikipedia).