An 'Achilles Heel' for Gonorrhea Infection?

Drug-resistant gonorrhea continues to evolve as an emerging infectious disease threat globally as efficacy of first-line drugs wanes.

“The main concern is that we are marching through classes of antibiotics for treatment. Several drugs have been available, but gonorrhea has rapidly acquired resistance with use of these drugs,” Christine Johnston, MD, MPH, FIDSA, medical director of the University of Washington Sexually Transmitted Diseases (STD) Prevention Training Center, part of the US Centers for Disease Control and Prevention (CDC)-funded National Network of STD Clinical Prevention Training Centers, told Contagion^® last year.

One way to combat resistance is to prevent infection in the first place. Investigators at the Institute for Biomedical Sciences at Georgia State University recently sought to evaluate what factors affect growth of Neisseria gonorrhoeae and determined that 1 of those elements is the uptake of the mineral zinc. Their findings were published in the journal PLoS Pathogens.

“Blocking metal uptake by the pathogen that causes the common sexually transmitted infection gonorrhea may be the pathogen’s ‘Achilles heel,’” Cynthia Nau Cornelissen, PhD, senior author of the study and director of the Center for Translational Immunology in the Institute for Biomedical Sciences, professor in the Institute for Biomedical Sciences and a distinguished university professor at Georgia State, told Contagion^®. “We think that blocking the transport of critical metals into the cell by either therapeutics or vaccination could be a way to prevent growth and therefore infection by N gonorrhoeae.”

N gonorrhoeae infection is particularly tricky to treat and prevent because of the pathogen’s series of outer membrane transporters, some of which are involved in the procurement of iron or iron chelates, while others—specifically TdfH and TdfJ—facilitate zinc uptake, according to Cornelissen and colleagues.

In a previous study, the research team found that the outer membrane transporter that was produced under zinc-depleted conditions enabled N gonorrhoeae to internalize zinc from a human protein called calprotectin, Cornelissen explained. In the new study, the team hypothesized that another zinc-repressed outer membrane transporter similarly interacted with an S100 metal binding protein.

“We demonstrated that a very well-conserved transporter, TdfJ, binds to S100A7, that this binding is human specific, and [that it] cannot be blocked by competition with the mouse form of S100A7,” Cornelissen said. “We demonstrated that providing zinc-bound S100A7 enables the wild-type gonococcal strain to grow, but a TdfJ mutant is prevented from growth on S100A7-zinc. We also importantly showed that when TdfJ is produced in Escherichia coli, we could reconstitute S100A7 binding. These observations indicate that TdfJ is both necessary and sufficient for S100A7 binding.”

Essentially, starving N gonorrhoeae of zinc will stop its growth within the host’s body.

With the help of a $9.25 million grant from the National Institutes of Health's National Institute of Allergy and Infectious Diseases, Cornelissen “aims to eventually develop a vaccine that blocks uptake of both iron and zinc by N gonorrhoeae and fully protects the host against this bacterial pathogen,” according to a Georgia State press release.

“Our plans are to continue to define the structure/function relationships in the interaction between TdfJ and S100A7,” she said. “We plan to explore whether TdfJ and similar outer membrane transporters could be components of a protective vaccine to prevent gonorrhea and its downstream sequelae, including pelvic inflammatory disease and infertility.”