EXECUTIVE SUMMARY

About 820,000 new gonococcal infections occur in the United States each year, with some 570,000 appearing in young people ages 15-24. In an effort to stem the tide of infection, science has identified a potential new treatment, which uses a peptide to disrupt an enzyme the microbe needs to respirate.

  • N. gonorrhoeae has developed resistance to each of the antimicrobials used for treatment, which presents a public health challenge. Because of declining susceptibility to cefixime, the Centers for Disease Control and Prevention’s latest guidelines now call for dual therapy with ceftriaxone (an injectable cephalosporin) and azithromycin as the sole recommended treatment regimen for gonorrhea.

About 820,000 new gonococcal infections occur in the United States each year, with some 570,000 appearing in young people ages 15-24.1 In an effort to stem the tide of infection, science has identified a potential new treatment, which uses a peptide to disrupt an enzyme the microbe needs to respirate.2

Researchers at Oregon State University in Corvallis, OR, have identified a new therapy target, an enzyme known as AniA. The Neisseria gonorrhoeae bacteria need the surface-exposed enzyme to respirate without oxygen in the biofilms of the genitourinary tract.

Aleksandra Sikora, PhD, MSc, associate professor in the university’s College of Pharmacy, and her team have focused on a peptide that inhibits the AniA enzyme’s nitrite reductase activity. This disruption in activity damages the bacteria’s ability to grow in the oxygen-poor biofilm environment.

Bacteria in biofilms display increased resistance to antimicrobials, explains Sikora. The enzyme is only necessary for cell viability when these bacteria grow under anaerobic conditions, including when they grow in the biofilm, she notes. “Most antibiotics target essential cell functions; this one doesn’t,” said Sikora in a statement accompanying the study publication. “It’s only at a certain stage of growth that the bacteria are affected, which means the development of resistance won’t be as fast.”

Scientists at the university, in collaboration with researchers at the University of Kentucky, have identified 29 unique peptides that bond with the targeted enzyme. A particular peptide, C7-3, has been earmarked as the most promising for inhibiting the protein’s interaction with nitrite, which is required for anaerobic respiration. Sikora has applied for a provisional patent in continuing work with use of the peptide.

Pressing for New Treatments

N. gonorrhoeae has developed resistance to each of the antimicrobials used to treat gonorrhea, which presents a public health challenge. Because of declining susceptibility to cefixime, the Centers for Disease Control and Prevention’s (CDC’s) latest guidelines guidelines now call for dual therapy with ceftriaxone (an injectable cephalosporin) and azithromycin as the sole CDC-recommended treatment regimen for gonorrhea.3

Health officials now have identified a cluster of gonorrhea infections that demonstrates decreased susceptibility to ceftriaxone and very high-level resistance to azithromycin. Laboratory tests conducted on gonorrhea isolates collected from seven individuals in Honolulu in 2016 indicated resistance to azithromycin at higher levels than typically are seen in the United States; also, isolates from five of the patients showed reduced susceptibility to ceftriaxone. Although all of the patients were treated successfully with the dual treatment regimen, the occurrence of a cluster of cases, which indicates that the strain was able to spread, and the resistance pattern are reasons for concern to public health officials.4 (Contraceptive Technology Update reported on the incident; see the January 2017 article, “STDs at Unprecedented High in United States,” available at: http://bit.ly/2hrYtkh.)

An interdisciplinary team from the United Kingdom-based University of York’s departments of biology and chemistry are focusing on what they term the “target room” of Neisseria gonorrhoeae. Since it is more sensitive to carbon monoxide-based toxicity than other model bacterial pathogens, it may be a possible candidate for therapy using carbon monoxide-releasing molecules. The carbon monoxide molecule works by binding to the bacteria, and preventing them from producing energy.5

“The carbon monoxide molecule targets the engine room, stopping the bacteria from respiring,” said Ian Fairlamb, PhD, a professor in the university’s department of chemistry, in a press statement. “Gonorrhoea only has one enzyme that needs inhibiting; [when] it can’t respire oxygen, it dies.”

The research team says the next step is to develop a drug so that the research findings can be translated on to clinical trials in the future.

“Antimicrobial resistance is a massive global problem which isn’t going away,” said James Moir, PhD, professor in the university’s department of biology, in a statement accompanying the data publication. “We need to use many different approaches, and the development of new drugs using bioinorganic chemistry is one crucial way we can tackle this problem, to control important bacterial pathogens before the current therapies stop working.”

REFERENCES

  1. Satterwhite CL, Torrone E, Meites E, et al. Sexually transmitted infections among US women and men: Prevalence and incidence estimates, 2008. Sex Transm Dis 2013;40:187-193.
  2. Sikora AE, Mills RH, Weber JV, et al. Peptide inhibitors targeting the Neisseria gonorrhoeae pivotal anaerobic respiration factor AniA. Antimicrob Agents Chemother 2017; doi: 10.1128/AAC.00186-17.
  3. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64(No. RR-3):1-137.
  4. Katz A, Komeya A, Tomas J, et al. Cluster of Neisseria gonorrhoeae isolates with high-level azithromycin resistance and decreased ceftriaxone susceptibility. Presented at the 2016 National STD Prevention Conference. Atlanta; September 2016.
  5. Ward JS, Morgan R, Lynam JM, et al. Toxicity of tryptophan manganese carbonyl (Trypto-CORM) against Neisseria gonorrhoeae. Med Chem Commun 2017;18:346-352.