During the past 50 years, the use of antimicrobial drugs to treat infections has become increasingly widespread. In response, microbes have been evolving to develop defenses, and as a result, those drugs are no longer effective in killing them. Although methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent drug-resistant infections, other diseases, like TB and malaria, are also becoming increasingly difficult to treat because of drug resistance.
In recent years, drug-resistant forms of gonorrhea, the second most commonly reported infectious disease in the United States, have begun to emerge. NIAID is investigating several angles to learn why the bacteria that cause gonorrhea are becoming resistant to treatments and studying new ways to treat and prevent the disease.
Gonorrhea is a sexually transmitted disease caused by Neisseria gonorrhoeae, a bacterium that can infect areas of the reproductive tract, including the cervix, uterus, and fallopian tubes in women, and the urethra, mouth, throat, eyes, and anus of both men and women. If left untreated, gonorrhea can lead to pelvic inflammatory disease, ectopic pregnancy, infertility, and increased risk of HIV infection. Gonorrhea can also be passed from mother to child and cause blindness or life-threatening infections in the infant.
This bacterium is particularly good at picking up pieces of DNA from other bacteria, thereby altering its genetic makeup and sometimes resulting in new ways to evade antibiotics. By this process, different strains of N. gonorrhoeae have systematically become resistant to all but one class of antibiotics: cephalosporins. However, recent data suggest that even cephalosporins are becoming less effective against some strains found in the United States, Asia, and Europe (MMWR 60: 873-77, 2011; Antimicrob Agents Chemother 55: 3538, 2011; Euro Surveill 15, 2010). There is increasing concern that N. gonorrhoeae may develop resistance to all available antibiotics, resulting in untreatable gonorrhea.
Searching for Ways To Shut Down the Efflux Pump
NIAID-funded investigators are studying the molecular mechanics of how N. gonorrhoeae bacteria are able to defend themselves against antibiotics. Dr. William Shafer at Emory University is studying the efflux pump, a structure that evolved in several types of bacteria to pump antimicrobial compounds out of the organism before they can do any harm. This work could help in the development of new types of therapeutics that inhibit the activity of the pump.
Zeroing in on Genes
In addition to studying structural characteristics, NIAID researchers are also interested in the genetics of the bacteria. Recently, the NIAID Microbial Genome Sequencing Centers worked with several investigators to sequence the genomes of several strains of N. gonorrhoeae. This data will allow researchers to compare the genomes of resistant and sensitive strains and to possibly zero in on the genetic basis of resistance. A total of 14 genomes have been sequenced.
Evaluating New Treatment Options
Currently, the Centers for Disease Control and Prevention (CDC) recommends that most cases of gonorrhea in the United States be treated with a combination of two drugs: a cephalosporin and a second antibiotic (i.e., azithromycin or doxycycline). At this time of rising antibiotic resistance, it is important that more than one type of treatment be available for infections like gonorrhea so that if an infection is resistant to one type of drug, there are other options. NIAID is studying new ways to treat cephalosporin-resistant infections by using existing antibiotic therapies in combination (i.e., gentamicin and azithromycin vs. gemifloxacin and azithromycin). NIAID is also supporting studies evaluating new therapeutics for gonorrhea, including a Phase II trial of an investigational oral antibiotic (NCT02257918) and a Phase I trial assessing the pharmacokinetics of an oral next generation macrolide (NCT02348424). NIAID is partnering with the company developing this macrolide to support a Phase III trial (NCT02210325) comparing the novel antibiotic to standard treatment (intramuscular ceftriaxone plus oral azithromycin). Additionally, NIAID provides resources to eligible researchers to test novel and existing therapeutics in a mouse model of gonorrhea infection. Through this mechanism, scientists can obtain preliminary data on the ability of the product to prevent N. gonorrhoeae infection.
For current information on treatments for gonorrhea, read the CDC STD Treatment Guidelines.
Identifying Targets for Future Vaccines
A safe and effective vaccine for gonorrhea would help alleviate much of the urgent need for new and improved therapeutics. Dr. Cynthia Cornelissen, an NIAID-funded investigator at Virginia Commonwealth University, is working toward that goal. Currently, Dr. Cornelissen is studying two proteins as potential vaccine targets. These two proteins help the bacteria utilize iron and are expressed by all strains of N. gonorrhoeae. After further analysis, if these two proteins are found to be essential for the survival of N. gonorrhoeae, they may be identified as valuable vaccine targets. A vaccine that is designed to knock out these proteins and prevent the development of the bacteria would be a step forward for researchers in both the gonorrhea and antimicrobial resistance fields.
Publications from these research projects include
- DeRocco AJ, Yost-Daljev MK, Kenney CD, Cornelissen CN. 2009. Kinetic analysis of ligand interaction with the gonococcal transferrin-iron acquisition system. Biometals. 22:439-451.
- Folster JP, Johnson PJT, Jackson L, Dhulipali V, Dyer DW, Shafer WM. 2009. MtrR modulates rpoH expression and levels of antimicrobial resistance in Neisseria gonorrhoeae. J Bacteriol. 191:287-297.
- Cornelissen CN. 2008. Identification and characterization of gonococcal iron transport systems as potential vaccine antigens. Future Microbiol. 3:287-298.
- Long F, Rouquette-Loughlin C, Shafer WM, Yu EW. 2008. Functional cloning and characterization of the multidrug efflux pumps NorM from Neisseria gonorrhoeae and YdhE from Escherichia coli. Antimicrob Agents Chemother. 52:3052-3060.
- Warner DM, Shafer WM, Jerse AE. 2008. Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae MtrC-MtrD-MtrE efflux pump system confer different levels of antimicrobial resistance and in vivo fitness. Mol Microbiol. 70:462-478.
- Mercante AD, Jackson L, Johnson PJ, Stringer VA, Dyer DW, Shafer WM. 2012. MpeR regulates the mtr efflux locus in Neisseria gonorrhoeae and modulates antimicrobial resistance by an iron-responsive mechanism. Antimicrob Agents Chemother.
- Ohneck EA, Zalucki YM, Johnson PJ, Dhulipala V, Golparian D, Unemo M, Jerse AE, Shafer WM. 2011. A novel mechanism of high-level, broad-spectrum antibiotic resistance caused by a single base pair change in Neisseria gonorrhoeae. MBio.M Sep 20;2(5).
- Price GA, Masri HP, Hollander AM, Russell MW, Cornelissen CN. 2007. Gonococcal transferring binding protein chimeras induce bactericidal and growth inhibitory antibodies in mice. Vaccine. 25:7247-7260.