Medical University of South Carolina study: How gonorrhea develops resistance to antibiotics

25 Aug

Medline summarized sexually transmitted diseases (STD):

Summary
Sexually transmitted diseases (STDs) are infections that are passed from one person to another through sexual contact. The causes of STDs are bacteria, parasites, yeast, and viruses. There are more than 20 types of STDs, including
• Chlamydia
• Genital herpes
• Gonorrhea
• HIV/AIDS
• HPV
• Syphilis
• Trichomoniasis
Most STDs affect both men and women, but in many cases the health problems they cause can be more severe for women. If a pregnant woman has an STD, it can cause serious health problems for the baby.
Antibiotics can treat STDs caused by bacteria, yeast, or parasites. There is no cure for STDs caused by a virus, but medicines can often help with the symptoms and keep the disease under control.
Correct usage of latex condoms greatly reduces, but does not completely eliminate, the risk of catching or spreading STDs. The most reliable way to avoid infection is to not have anal, vaginal, or oral sex.
Centers for Disease Control and Prevention https://medlineplus.gov/sexuallytransmitteddiseases.html

Helen Adams reported in Skyrocketing STDs have doctors urging sexually active young people to be tested:

MUSC Health obstetrician and gynecologist Jessica Tarleton has seen a lot in her role as a reproductive infectious disease specialist, but even she is stunned by new STD statistics released by the Centers for Disease Control and Prevention. “A lot of these infections are in young people, very young people.”
This week, the CDC reported there were almost 2.3 million cases of chlamydia, gonorrhea and syphilis in the United States last year….
• Chlamydia is the most common, with more than 1.7 million cases last year.
• Gonorrhea diagnoses rose 67 percent between 2013 and 2017, hitting 555,608 last year.
• Syphilis jumped 76 percent during that same time period, hitting 30,644 cases last year.

Here’s why getting tested matters. A lot of people who have STDs don’t have any symptoms or don’t realize their rashes and other issues are linked to STDs. So if they don’t get tested regularly, the disease can progress. Chlamydia and gonorrhea can cause infertility in women if left untreated. Syphilis can cause neurological problems in both women and men, Tarleton says. And it can do more than that.

“One of the things that’s most upsetting to me is the rate of syphilis we’re seeing in pregnant women, because that can have severe effects on the fetus and baby. Babies can have congenital birth defects, some bone malformations, blindness and deafness. Sometimes it can lead to miscarriage or fetal death in utero. This can happen in moms who don’t know they have it.”

The good news is, all three STDs are treatable with antibiotics, although there is concern that gonorrhea is becoming antibiotic resistant.

So what’s going on? Why is the U.S. seeing a surge in STDs to the point that it’s being called a public health crisis?

Tarleton says part of the problem is some of the people at risk of getting STDs, young people, don’t know enough to worry about them. “Our teenagers are kind of going out unequipped to protect themselves from getting these infections.”

Other factors causing the rise in STDs, cited in a national discussion this week at the CDC’s 2018 STD Prevention Conference, include:

• A lack of funding for prevention programs.
• The opioid epidemic, which is causing some women to trade sex for drugs.
• Methamphetamines and other drugs, which are linked to forced sex, sex for money and sex with people who inject drugs.
• Doctors and patients who are reluctant to talk about STDs….

Tarleton says the best way to prevent STDs is to use condoms. “Condoms are still a very effective way of preventing the spread of sexually transmitted infections. And we want people to take seriously the need for screening and treatment of themselves and their sexual partners. I don’t think the message has been getting out, and it’s becoming a bigger and bigger problem.”
https://web.musc.edu/about/news-center/2018/08/31/skyrocketing-stds-have-doctors-urging-sexually-active-young-people-to-be-tested

Resources:

Your Guide to Sexually Transmitted Diseases                                            https://www.webmd.com/sexual-conditions/guide/sexual-health-stds#1

Sexually Transmitted Diseases                                                     https://www.drugs.com/cg/sexually-transmitted-diseases.html

Symptoms and Signs of Sexually Transmitted Diseases (STDs)
Privacy & Trust Info
Doctor’s Notes on Sexually Transmitted Diseases (STDs) https://www.emedicinehealth.com/sexually_transmitted_diseases/symptom.htm

Sexually Transmitted Diseases (STDs)                                        https://www.cdc.gov/std/default.htm

Science Daily reported in How gonorrhea develops resistance to antibiotics:

Steadily and relentlessly, the bacterium that causes gonorrhea has slipped past medicine’s defenses, acquiring resistance to once-reliable drugs, including penicillin, tetracycline, and ciprofloxacin. These former stalwarts are no longer used to treat the sexually transmitted disease.
In 2010, after some strains of Neisseria gonorrhoeae, the bacterium responsible for gonorrhea, began showing resistance to one of the last remaining classes of antibiotics, the Centers for Disease Control and Prevention began recommending “dual therapy,” meaning that doctors now prescribe two drugs at the same time to fight gonorrhea. Currently, those two drugs are ceftriaxone, a member of the cephalosporin class of antibiotics, and azithromycin.
With fears increasing that gonorrhea could breach these last defenses, the work of researchers like crystallographer Christopher Davies, Ph.D., is crucial.
“We’re looking at a molecular level at the events that have got everybody worried out there in the clinics,” said Davies, a professor in the Department of Biochemistry & Molecular Biology and director of the MUSC Center for Structural Biology.
Davies’ team has just published a paper showing how cephalosporins bind and inactivate a gonococcal protein dubbed penicillin-binding protein 2 (PBP2). Led by postdoctoral fellow Avinash Singh, Ph.D., the researchers showed the protein undergoes key structural changes, including twisting and rolling of a loop to bind the antibiotic, that enhance the reaction with cephalosporins. Without these changes, the protein would react much more slowly with the antibiotic.
Davies explained that all antibiotics work by targeting essential functions in a particular bug. Cephalosporins work by attacking the bacterial cell wall.
Normally, PBP2 moves along the bacterial cell’s cytoplasmic membrane, reaching out into the space between the cytoplasmic membrane and the outer membrane, looking for peptides to bind to. The protein joins peptides together to create a mesh — just like an onion bag at the grocery store, Davies said. But antibiotics jump in to bind to the protein before it can get to a peptide.
“The protein is walking around the membrane layer as normal, but its active site is blocked by antibiotic, so all those potential interactions with the peptide substrate are fruitless,” Davies said.
With the protein out of commission and not building the mesh, holes start to appear in the cell wall. Cytoplasm starts to leak out, and the cell bursts and dies, Davies said.
Yet the resistant strains, which have been identified in Japan, France, Spain and most recently in Canada, evade the lethal action of cephalosporins by preventing the antibiotic from binding to the protein target. How they achieve this is a major focus of Davies’ research.
There are 60-some mutations on the PBP2 protein in the resistant strains of gonorrhea. Davies’ team has identified six mutations that are at the root of the resistance and is looking at how the mutations change the way the protein reacts to antibiotics…. https://www.sciencedaily.com/releases/2019/08/190823140704.htm

Citation:

How gonorrhea develops resistance to antibiotics
Date: August 23, 2019
Source: Medical University of South Carolina
Summary:
As public health officials worry about the emergence of antibiotic-resistant gonorrhea, researchers are tracing how antibiotics bind to a gonococcal protein, information that can help lead to new antimicrobials.

Journal Reference:
Avinash Singh, Joshua Tomberg, Robert A Nicholas, Christopher Davies. Recognition of the β-lactam Carboxylate Triggers Acylation of Neisseria gonorrhoeae Penicillin-Binding Protein 2. Journal of Biological Chemistry, 2019; jbc.RA119.009942 DOI: 10.1074/jbc.RA119.009942

Here is the press release from Medical University of South Carolina:

Researcher works to understand how gonorrhea develops resistance to antibiotics

Leslie Cantu

August 23, 2019

Steadily and relentlessly, the bacterium that causes gonorrhea has slipped past medicine’s defenses, acquiring resistance to once-reliable drugs, including penicillin, tetracycline and ciprofloxacin. These former stalwarts are no longer used to treat the sexually transmitted disease.
In 2010, after some strains of Neisseria gonorrhoeae, the bacterium responsible for gonorrhea, began showing resistance to one of the last remaining classes of antibiotics, the Centers for Disease Control and Prevention began recommending “dual therapy,” meaning that doctors now prescribe two drugs at the same time to fight gonorrhea. Currently, those two drugs are ceftriaxone, a member of the cephalosporin class of antibiotics, and azithromycin.

With fears increasing that gonorrhea could breach these last defenses, the work of researchers like crystallographer Christopher Davies, Ph.D., is crucial.

“We’re looking at a molecular level at the events that have got everybody worried out there in the clinics,” said Davies, a professor in the Department of Biochemistry & Molecular Biology and director of the MUSC Center for Structural Biology.

Davies’ team has just published a paper showing how cephalosporins bind and inactivate a gonococcal protein dubbed penicillin-binding protein 2 (PBP2). Led by postdoctoral fellow Avinash Singh, Ph.D., the researchers showed the protein undergoes key structural changes, including twisting and rolling of a loop to bind the antibiotic, that enhance the reaction with cephalosporins. Without these changes, the protein would react much more slowly with the antibiotic.

Davies explained that all antibiotics work by targeting essential functions in a particular bug. Cephalosporins work by attacking the bacterial cell wall.

Normally, PBP2 moves along the bacterial cell’s cytoplasmic membrane, reaching out into the space between the cytoplasmic membrane and the outer membrane, looking for peptides to bind to. The protein joins peptides together to create a mesh – just like an onion bag at the grocery store, Davies said. But antibiotics jump in to bind to the protein before it can get to a peptide.

“The protein is walking around the membrane layer as normal, but its active site is blocked by antibiotic, so all those potential interactions with the peptide substrate are fruitless,” Davies said.

With the protein out of commission and not building the mesh, holes start to appear in the cell wall. Cytoplasm starts to leak out, and the cell bursts and dies, Davies said.

Yet the resistant strains, which have been identified in Japan, France, Spain and most recently in Canada, evade the lethal action of cephalosporins by preventing the antibiotic from binding to the protein target. How they achieve this is a major focus of Davies’ research.
There are 60-some mutations on the PBP2 protein in the resistant strains of gonorrhea. Davies’ team has identified six mutations that are at the root of the resistance and is looking at how the mutations change the way the protein reacts to antibiotics.

Once researchers understand how the mutations are preventing antibiotics from doing their work, new drugs can be developed, Davies said. Knowing which mutations are important may also allow a diagnostic test to be developed to tell doctors whether a particular patient has a resistant strain and, therefore, which drugs to prescribe.

Davies said it appears that the mutations restrict the protein’s flexibility, preventing the structural changes needed to bind the antibiotic. That triggers a new mystery. If those movements are critical to its job of binding to peptides and building the mesh that keeps the cell wall intact, how can the mutations block the antibiotic but still allow the normal reaction? “This is the most fascinating aspect of our research,” Davies said.

“It’s an essential function, so the mutations can’t change the protein too much. It must be able to discriminate. Discriminating against an antibiotic while still retaining the normal binding and reaction with their substrate is a delicate balancing act they have to negotiate,” he said.

This balancing act might be the reason that antibiotic-resistant gonorrhea hasn’t spread as quickly as anticipated.

“There’s a fitness cost. They don’t function quite as well as their susceptible counterparts, and it’s probably for that reason they’re not spreading as fast as people feared they would,” Davies said.

Although the resistant-type gonorrhea isn’t spreading as quickly as public health officials feared, there have been increases in the number of cases of susceptible gonorrhea, as well as other sexually transmitted diseases.

Gonorrhea diagnoses increased by 67% between 2013 and 2017, according to the CDC.

“We expect gonorrhea will eventually wear down our last highly effective antibiotic, and additional treatment options are urgently needed,” said Gail Bolan, M.D., director of the CDC’s Division of STD Prevention, when it released those figures.

South Carolina has the fourth highest rate of gonorrhea in the U.S., according to an analysis of CDC numbers by Health Testing Centers, a lab testing service.
MUSC infectious disease specialist Eric Meissner, M.D., Ph.D., said it’s not entirely clear why the rates of STDs are increasing.

“We know that there are proven interventions that individuals can use, including regular use of condoms, that markedly reduce the odds of acquiring a sexually transmitted disease. So the rise in STD rates suggests there’s a need for more public health interventions and education,” he said.

Although gonorrhea isn’t fatal, it can cause lifelong problems if left untreated, including infertility and susceptibility to other sexually transmitted diseases, like HIV.

“An important thing for people to know is you can have gonorrhea and not have symptoms, so you can’t rely upon the absence of symptoms alone to provide reassurance that you or your sexual partner do not have gonorrhea,” Meissner said. “Sexually active people at risk for gonorrhea exposure should get regular testing”.

Meanwhile, Davies and his team are continuing their work in the lab. The next step is understanding how the protein can still perform its normal essential function while eluding the antibiotics. The group has some ideas that it will put to the test, he said.

Meissner said antibiotic resistance is concerning to doctors in the clinic.

“Even though the specific strain Dr. Davies is studying is rare, it is important to note that the emergence of resistance in gonorrhea is a real concern,” Meissner said.

About the Author
Leslie Cantu
Keywords: Research
Contact Us 843-792-2300 https://web.musc.edu/about/news-center/2019/08/23/antibiotic-resistant-gonorrhea-research

The Mayo Clinic summarized treatment for STDs:

Diagnosis
Tests
If your sexual history and current signs and symptoms suggest that you have a sexually transmitted disease (STD) or a sexually transmitted infection (STI), laboratory tests can identify the cause and detect coinfections you might also have.
• Blood tests. Blood tests can confirm the diagnosis of HIV or later stages of syphilis.
• Urine samples. Some STIs can be confirmed with a urine sample.
• Fluid samples. If you have open genital sores, your doctor may test fluid and samples from the sores to diagnose the type of infection.
Screening
Testing for a disease in someone who doesn’t have symptoms is called screening. Most of the time, STI screening is not a routine part of health care, but there are exceptions:
• Everyone. The one STI screening test suggested for everyone ages 13 to 64 is a blood or saliva test for human immunodeficiency virus (HIV), the virus that causes AIDS. Experts recommend that people at high risk have an HIV test every year.
• Everyone born between 1945 and 1965. There’s a high incidence of hepatitis C in people born between 1945 and 1965. Since the disease often causes no symptoms until it’s advanced, experts recommend that everyone in that age group be screened for hepatitis C.
• Pregnant women. All pregnant women will generally be screened for HIV, hepatitis B, chlamydia and syphilis at their first prenatal visit. Gonorrhea and hepatitis C screening tests are recommended at least once during pregnancy for women at high risk of these infections.
• Women age 21 and older. The Pap test screens for cervical abnormalities, including inflammation, precancerous changes and cancer, which is often caused by certain strains of human papillomavirus (HPV). Experts recommend that women have a Pap test every three years starting at age 21. After age 30, experts recommend women have an HPV DNA test and a Pap test every five years. A Pap test every three years is also acceptable.
• Women under age 25 who are sexually active. Experts recommend that all sexually active women under age 25 be tested for chlamydia infection. The chlamydia test uses a sample of urine or vaginal fluid you can collect yourself.
Some experts recommend repeating the chlamydia test three months after you’ve had a positive test and been treated. Reinfection by an untreated or undertreated partner is common, so you need the second test to confirm that the infection is cured. You can catch chlamydia multiple times, so get retested if you have a new partner.
Screening for gonorrhea is also recommended in sexually active women under age 25.
• Men who have sex with men. Compared with other groups, men who have sex with men run a higher risk of acquiring STIs. Many public health groups recommend annual or more-frequent STI screening for these men. Regular tests for HIV, syphilis, chlamydia and gonorrhea are particularly important. Evaluation for hepatitis B also may be recommended.
• People with HIV. If you have HIV, it dramatically raises your risk of catching other STIs. Experts recommend immediate testing for syphilis, gonorrhea, chlamydia and herpes after being diagnosed with HIV. They also recommend that people with HIV be screened for hepatitis C.
Women with HIV may develop aggressive cervical cancer, so experts recommend they have a Pap test within a year of being diagnosed with HIV, and then again six months later.
• People who have a new partner. Before having vaginal or anal intercourse with new partners, be sure you’ve both been tested for STIs. However, routine testing for genital herpes isn’t recommended unless you have symptoms.
It’s also possible to be infected with an STI yet still test negative, particularly if you’ve recently been infected.
More Information
• STD testing
• Complete blood count (CBC)
• HIV testing
Show More
Treatment
Sexually transmitted diseases (STDs) or sexually transmitted infections (STIs) caused by bacteria are generally easier to treat. Viral infections can be managed but not always cured. If you are pregnant and have an STI, getting treatment right away can prevent or reduce the risk of your baby becoming infected.
Treatment for STIs usually consists of one of the following, depending on the infection:
• Antibiotics. Antibiotics, often in a single dose, can cure many sexually transmitted bacterial and parasitic infections, including gonorrhea, syphilis, chlamydia and trichomoniasis. Typically, you’ll be treated for gonorrhea and chlamydia at the same time because the two infections often appear together.
Once you start antibiotic treatment, it’s necessary to follow through. If you don’t think you’ll be able to take medication as prescribed, tell your doctor. A shorter, simpler course of treatment may be available.
In addition, it’s important to abstain from sex until seven days after you’ve completed antibiotic treatment and any sores have healed. Experts also suggest women be retested in about three months because there’s high chance of reinfection.
• Antiviral drugs. If you have herpes or HIV, you’ll be prescribed an antiviral drug. You’ll have fewer herpes recurrences if you take daily suppressive therapy with a prescription antiviral drug. However, it’s still possible to give your partner herpes.
Antiviral drugs can keep HIV infection in check for many years. But you will still carry the virus and can still transmit it, though the risk is lower.
The sooner you start treatment, the more effective it is. If you take your medications exactly as directed, it’s possible to reduce your virus count so low that it can hardly be detected.
If you’ve had an STI, ask your doctor how long after treatment you need to be retested. Getting retested will ensure that the treatment worked and that you haven’t been reinfected.
Partner notification and preventive treatment
If tests show that you have an STI, your sex partners — including your current partners and any other partners you’ve had over the last three months to one year — need to be informed so that they can get tested. If they’re infected, they can then be treated.
Each state has different requirements, but most states require that certain STIs be reported to the local or state health department. Public health departments often employ trained disease intervention specialists who can help notify partners and refer people for treatment…. https://www.mayoclinic.org/diseases-conditions/sexually-transmitted-diseases-stds/diagnosis-treatment/drc-20351246

Resources:

What are the treatments for sexually transmitted diseases and sexually transmitted infections (STDs/STIs)? https://www.nichd.nih.gov/health/topics/stds/conditioninfo/treatments

Treatments for Sexually Transmitted Diseases (STDs)                   https://www.webmd.com/sexual-conditions/guide/std-treatments#1

IF YOU ARE AT RISK FOR A SEXUALLY TRANSMITTED DISEASE OR FEEL YOU HAVE ALREADY CONTRACTED AN STD – SEEK MEDICAL ATTENTION.

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