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''Mycoplasma genitalium'' (''MG'', commonly known as Mgen) is a
sexually transmitted Sexually transmitted infections (STIs), also referred to as sexually transmitted diseases (STDs) and the older term venereal diseases, are infections that are spread by sexual activity, especially vaginal intercourse, anal sex, and oral ...
, small and
pathogenic In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ger ...
bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
that lives on the mucous
epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
of the urinary and genital tracts in humans. Medical reports published in 2007 and 2015 state that Mgen is becoming increasingly common. Resistance to multiple
antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and preventio ...
is becoming prevalent, including to azithromycin, which until recently was the most reliable treatment. The bacteria was first isolated from the
urogenital tract The genitourinary system, or urogenital system, are the organs of the reproductive system and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathwa ...
of humans in 1981, and was eventually identified as a new species of ''
Mycoplasma ''Mycoplasma'' is a genus of bacteria that, like the other members of the class '' Mollicutes'', lack a cell wall around their cell membranes. Peptidoglycan ( murein) is absent. This characteristic makes them naturally resistant to antibioti ...
'' in 1983. It can cause negative health effects in men and women. It also increases the risk factor for HIV spread with higher occurrences in those previously treated with the azithromycin
antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and preventio ...
. Specifically, it causes urethritis in both men and women, and also cervicitis and pelvic inflammation in women. It presents clinically similar symptoms to that of '' Chlamydia trachomatis'' infection and has shown higher incidence rates, compared to both ''Chlamydia trachomatis'' and ''
Neisseria gonorrhoeae ''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular), or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gon ...
'' infections in some populations. Its complete genome sequence was published in 1995 (size 0.58 Mbp, with 475 genes). It was regarded as a cellular unit with the smallest genome size (in Mbp) until 2003 when a new species of
Archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...
, namely '' Nanoarchaeum equitans'', was sequenced (0.49 Mbp, with 540 genes). However, Mgen still has the smallest genome of any known (naturally occurring)
self-replicating Self-replication is any behavior of a dynamical system that yields construction of an identical or similar copy of itself. Biological cells, given suitable environments, reproduce by cell division. During cell division, DNA is replicated and ca ...
organism and thus is often the organism of choice in minimal genome research. The synthetic genome of Mgen named ''Mycoplasma genitalium'' JCVI-1.0 (after the research centre, J. Craig Venter Institute, where it was synthesised) was produced in 2008, becoming the first organism with a synthetic genome.


Signs and symptoms

Infection with Mgen produces a combination of clinical symptoms, but can be
asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered a ...
. It causes
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
in the
urethra The urethra (from Greek οὐρήθρα – ''ourḗthrā'') is a tube that connects the urinary bladder to the urinary meatus for the removal of urine from the body of both females and males. In human females and other primates, the urethra ...
( urethritis) both in men and women, which is associated with mucopurulent discharge in the
urinary tract The urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressure, c ...
, and burning while urinating. In women, it causes cervicitis and pelvic inflammatory diseases (PID), including
endometritis Endometritis is inflammation of the inner lining of the uterus (endometrium). Symptoms may include fever, lower abdominal pain, and abnormal vaginal bleeding or discharge. It is the most common cause of infection after childbirth. It is also pa ...
and
salpingitis Salpingitis is an infection causing inflammation in the Fallopian tubes (also called ''salpinges''). It is often included in the umbrella term of pelvic inflammatory disease (PID), along with endometritis, oophoritis, myometritis, parametritis, an ...
. Women may also experience bleeding after sex and it is also linked with tubal factor infertility. For men, the most common signs are painful urination or a watery discharge from the penis.
Polymerase chain reaction The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) ...
analyses indicated that it is a cause of acute non-gonococcal urethritis (NGU) and probably chronic NGU. It is strongly associated with persistent and recurring non-gonococcal urethritis (NGU) responsible for 15 percent to 20 percent of symptomatic NGU cases in men. Unlike other ''Mycoplasma'', the infection is not associated with
bacterial vaginosis Bacterial vaginosis (BV) is a disease of the vagina caused by excessive growth of bacteria. Common symptoms include increased vaginal discharge that often smells like fish. The discharge is usually white or gray in color. Burning with urinati ...
. It is highly associated with the intensity of HIV infection. Some scientists are performing research to determine if Mgen could play a role in the development of prostate and
ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
s and lymphomas in some individuals. These studies have yet to find conclusive evidence to suggest a link.


Genome

The genome of ''M. genitalium'' consists of 525 genes in one circular DNA of 580,070
base pairs A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DN ...
. Scott N. Peterson and his team at the
University of North Carolina at Chapel Hill A university () is an institution of higher (or tertiary) education and research which awards academic degrees in several academic disciplines. Universities typically offer both undergraduate and postgraduate programs. In the United State ...
reported the first genetic map using
pulsed-field gel electrophoresis Pulsed field gel electrophoresis is a technique used for the separation of large DNA molecules by applying to a gel matrix an electric field that periodically changes direction. Historical background Standard gel electrophoresis techniques for s ...
in 1991. They performed an initial study of the genome using random sequencing in 1993, by which they found 100,993 nucleotides and 390 protein-coding genes. Collaborating with researchers at the
Institute for Genomic Research The J. Craig Venter Institute (JCVI) is a non-profit genomics research institute founded by J. Craig Venter, Ph.D. in October 2006. The institute was the result of consolidating four organizations: the Center for the Advancement of ...
, which included
Craig Venter John Craig Venter (born October 14, 1946) is an American biotechnologist and businessman. He is known for leading one of the first draft sequences of the human genome and assembled the first team to transfect a cell with a synthetic chromosome. ...
, they made the complete genome sequence in 1995 using
shotgun sequencing In genetics, shotgun sequencing is a method used for sequencing random DNA strands. It is named by analogy with the rapidly expanding, quasi-random shot grouping of a shotgun. The chain-termination method of DNA sequencing ("Sanger sequencing ...
. Only 470 predicted
coding region The coding region of a gene, also known as the coding sequence (CDS), is the portion of a gene's DNA or RNA that codes for protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared to n ...
s (out of 482 protein encoding genes) were identified, including
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s required for
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritan ...
, transcription and
translation Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
,
DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
,
cellular transport A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane ...
, and energy metabolism. It was the second complete bacterial genome ever sequenced, after ''
Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bact ...
''. In 2006, the team at the J. Craig Venter Institute reported that only 382 genes are essential for biological functions. The small genome of ''M. genitalium'' made it the organism of choice in The Minimal Genome Project, a study to find the smallest set of genetic material necessary to sustain
life Life is a quality that distinguishes matter that has biological processes, such as signaling and self-sustaining processes, from that which does not, and is defined by the capacity for growth, reaction to stimuli, metabolism, energy ...
.


Pathophysiology

There is a consistent association of ''M. genitalium'' infection and female reproductive tract syndromes. ''M. genitalium'' infection was significantly associated with increased risk of preterm birth, spontaneous abortion, cervicitis, and pelvic inflammatory disease. In addition, this pathogen may latently infect the
chorionic villi Chorionic villi are villi that sprout from the chorion to provide maximal contact area with maternal blood. They are an essential element in pregnancy from a histomorphologic perspective, and are, by definition, a product of conception. Branche ...
tissues of pregnant women, thereby impacting pregnancy outcome. Infertility risk is also strongly associated with infection with ''M. genitalium'', although evidence suggests it is not associated with male infertility. When ''M. genitalium'' is a co-infectious agent risk associations are stronger and statistically significant. ''M. genitalium'' is strongly associated with HIV-1.


Diagnosis

Recent research shows that prevalence of Mgen is currently higher than other commonly occurring
sexually transmitted infection Sexually transmitted infections (STIs), also referred to as sexually transmitted diseases (STDs) and the older term venereal diseases, are infections that are spread by sexual activity, especially vaginal intercourse, anal sex, and ora ...
s (STIs). Mgen is a fastidious organism with prolonged growth durations. This makes detection of the pathogen in clinical specimens and subsequent isolation extremely difficult. Lacking a
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...
,
mycoplasma ''Mycoplasma'' is a genus of bacteria that, like the other members of the class '' Mollicutes'', lack a cell wall around their cell membranes. Peptidoglycan ( murein) is absent. This characteristic makes them naturally resistant to antibioti ...
remains unaffected by commonly used
antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and preventio ...
. The absence of specific serological assays leaves nucleic acid amplification tests (NAAT) as the only viable option for detection of Mgen DNA or RNA. However, samples with positive NAAT for the pathogen should be tested for
macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...
resistance
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s, which are strongly correlated to azithromycin treatment failures, owing to rapid rates of mutation of the pathogen. Mutations in the 23S rRNA gene of Mgen have been linked with clinical treatment failure and high level
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
macrolide resistance. Macrolide resistance mediating mutations have been observed in 20-50% of cases in the UK, Denmark, Sweden, Australia, and Japan. Resistance is also developing towards the second-line
antimicrobial An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ar ...
s like fluoroquinolone. According to the European guidelines, the indication for commencement of diagnosis for Mgen infection are: # Detection of nucleic acid (DNA and/or RNA) specific for Mgen in a clinical specimen # Current partners of individuals who tested positive for Mgen should be treated with the same antimicrobial as the
index patient The index case or patient zero is the first documented patient in a disease epidemic within a population, or the first documented patient included in an epidemiological study. It can also refer to the first case of a condition or syndrome (not ...
# If current partner does not attend for evaluation and testing, treatment with the same regimen as given to the index patient should be offered on
epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population. It is a cornerstone of public health, and shapes policy decisions and evid ...
grounds # On epidemiological grounds for sexual contacts in the previous 3 months; ideally, specimens for a Mgen NAAT should be collected before treatment and treatment should not be given before the result are available Screening for Mgen with a combination of detection and macrolide resistance mutations will provide the adequate information required to develop personalised antimicrobial treatments, in order to optimise patient management and control the spread of antimicrobial resistance (AMR).Tabrizi SN et al. Multiplex Assay for Simultaneous Detection of Mycoplasma genitalium and Macrolide Resistance Using PlexZyme and PlexPrime Technology. PLoS ONE. 2016. 11(6): e0156740. doi:10.1371/journal.pone.0156740


Detection of resistance

Owing to the widespread macrolide resistance, samples that are positive for Mgen should ideally be followed up with an assay capable of detecting mutations that mediate antimicrobial resistance. The European Guideline on Mgen infections, in 2016, recommended complementing the molecular detection of Mgen with an assay capable of detecting macrolide resistance-associated mutations.


Treatment

The U.S.
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georg ...
recommends a step-wise treatment approach for ''Mycoplasma genitalium'' with
doxycycline Doxycycline is a broad-spectrum tetracycline class antibiotic used in the treatment of infections caused by bacteria and certain parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus ...
for 7 days followed immediately by a 7-day course of
moxifloxacin Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop. Common side effects ...
as the preferred therapy due to high rates of macrolide resistance. If resistance assay testing is available, and the Mgen is sensitive to macrolides, the CDC recommends a 7-day course of doxycycline followed by a 4-day course of azithromycin. Although the majority of ''M. genitalium'' strains are sensitive to moxifloxacin, resistance has been reported, and potential for serious, adverse side effects should be considered with this regimen. Floroquinolones, including Moxifloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including: * Tendinitis and tendon rupture * Peripheral Neuropathy * Central nervous system effects and other serious side effects detailed in the FDA black box warning. Moxifloxacin/Avelox should be reserved for use when patients have no other treatment options. In settings without access to resistance testing, or if Moxifloxacin cannot be used, the CDC recommends as an alternative regimen: 7 days of doxycycline followed by the 4-day course of azithromycin, with a test of cure 21 days after treatment being required due to the high rate of macrolide resistance. Beta lactam antibiotics are not effective against Mgen as the organism lacks a cell wall. In the UK the British Association for Sexual Health and HIV (BASHH) guidelines for treatment are: *Doxycycline 100mg twice a day for seven days followed by azithromycin 1 gram orally as a single dose then 500mg orally once daily for 2 days where organism is known to be macrolide-sensitive or where resistance status is unknown. *Moxifloxacin 400mg orally once daily for 10 days if organism known to be macrolide-resistant or where treatment with azithromycin has failed. Treatment of ''Mycoplasma genitalium'' infections is becoming increasingly difficult due to rapidly growing antimicrobial resistance. Diagnosis and treatment is further hampered by the fact that ''Mycoplasma genitalium'' infections are not routinely tested. Studies have demonstrated that a 5-day course of azithromycin has a superior cure rate compared to a single, larger dose. Further, a single dose of azithromycin can lead to the bacteria becoming resistant to azithromycin. Among Swedish patients, doxycycline was shown to be relatively ineffective (with a cure rate of 48% for women and 38% for men); and treatment with a single dose of azithromycin is not prescribed due to it inducing antimicrobial resistance. The five-day treatment with azithromycin showed no development of antimicrobial resistance. Based on these findings, UK doctors are moving to the 5-day azithromycin regimen. Doxycycline is also still used, and
moxifloxacin Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop. Common side effects ...
is used as a second-line treatment in case doxycyline and azithromycin are not able to eradicate the infection. In patients where doxycycline, azithromycin and moxifloxacin all failed, pristinamycin has been shown to still be able to eradicate the infection.


History

''Mycoplasma genitalium'' was originally isolated in 1980 from urethral
specimen Specimen may refer to: Science and technology * Sample (material), a limited quantity of something which is intended to be similar to and represent a larger amount * Biological specimen or biospecimen, an organic specimen held by a biorepository f ...
s of two male patients with non-gonococcal urethritis in the genitourinary medicine (GUM) clinic at St Mary's Hospital, Paddington, London. It was reported in 1981 by a team led by Joseph G. Tully. Under electron microscopy, it appears as a flask-shaped cell with a narrow terminal portion that is crucial for its attachment to the host cell surfaces. The bacterial cell is slightly elongated somewhat like a vase, and measures 0.6–0.7 μm in length, 0.3–0.4 μm at the broadest region, and 0.06–0.08 μm at the tip. The base is broad while the tip is stretched into a narrow neck, which terminates with a cap. The terminal region has a specialised region called nap, which is absent in other ''Mycoplasma''. Serological tests indicated that the bacterium was not related to known species of ''Mycoplasma''. The comparison of genome sequences with other urinogenital bacteria, such as '' M. hominis'' and ''
Ureaplasma parvum ''Ureaplasma parvum'' is a species of '' Ureaplasma'', a genus of bacteria belonging to the family Mycoplasmataceae. In Indonesia, ureaplasma parvum is most commonly contracted through contact with public toilets. ''Ureaplasma parvum'' was form ...
'', revealed that ''M. genitalium'' is significantly different, especially in the energy-generating pathways, although it shared a core genome of ~250 protein-encoding genes.


Synthetic genome

On 6 October 2007,
Craig Venter John Craig Venter (born October 14, 1946) is an American biotechnologist and businessman. He is known for leading one of the first draft sequences of the human genome and assembled the first team to transfect a cell with a synthetic chromosome. ...
announced that a team of scientists led by Nobel laureate Hamilton Smith at the J. Craig Venter Institute had successfully constructed
synthetic DNA In September 2021, Synthetic Genomics Inc. (SGI), a private company located in La Jolla, California, changed its name to Viridos. The company is focused on the field of synthetic biology, especially harnessing photosynthesis with micro algae to ...
with which they planned to make the first synthetic genome. Reporting in ''
The Guardian ''The Guardian'' is a British daily newspaper. It was founded in 1821 as ''The Manchester Guardian'', and changed its name in 1959. Along with its sister papers '' The Observer'' and '' The Guardian Weekly'', ''The Guardian'' is part of the ...
'', Venter said that they had stitched together a DNA strand containing 381 genes, consisting of 580,000 base pairs, based on the genome of ''M. genitalium''. On 24 January 2008, they announced the successful creation of a synthetic bacterium, which they named ''Mycoplasma genitalium'' JCVI-1.0 (the name of the strain indicating J. Craig Venter Institute with its specimen number). They synthesised and assembled the complete 582,970-base pair genome of the bacterium. The final stages of synthesis involved cloning the DNA into the bacterium '' E. coli'' for nucleotide production and sequencing. This produced large fragments of approximately 144,000 base pairs or 1/4th of the whole genome. Finally, the products were cloned inside the yeast ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...
'' to synthesize the 580,000 base pairs. The molecular size of the synthetic bacterial genome is 360,110 kilodaltons (kDa). Printed in 10-point font, the letters of the genome cover 147 pages. On 20 July 2012,
Stanford University Stanford University, officially Leland Stanford Junior University, is a private research university in Stanford, California. The campus occupies , among the largest in the United States, and enrolls over 17,000 students. Stanford is conside ...
and the J. Craig Venter Institute announced successful simulation of the complete life cycle of a ''Mycoplasma genitalium'' cell, in the journal '' Cell''. The entire organism is modeled in terms of its molecular components, integrating all cellular processes into a single model. Using object oriented programming to model the interactions of 28 categories of molecules, including DNA, RNA, proteins, and metabolites, and running on a 128 computer Linux cluster, the simulation takes 10 hours for a single ''M. genitalium'' cell to divide once—about the same time the actual cell takes—and generates half a gigabyte of data.


Research

The discovery of Protein M, a new protein from ''M. genitalium'', was announced in February 2014. The protein was identified during investigations on the origin of
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ...
, a B-cell hematologic neoplasm. To understand the long-term ''Mycoplasma'' infection, it was found that
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
from multiple myeloma patients' blood were recognised by ''M. genitalium''. The antibody reactivity was due to a protein never known before, and is chemically responsive to all types of human and nonhuman antibodies available. The protein is about 50 kDa in size, and composed of 556 amino acids.


References


External links


''Mycoplasma genitalium'' Reference Work
at the UK Health Protection Agency
Type strain of ''Mycoplasma genitalium'' at Bac''Dive'' - the Bacterial Diversity Metadatabase
{{Use dmy dates, date=October 2019 genitalium Model organisms Organism size Sexually transmitted diseases and infections Synthetic biology Bacteria described in 1983 Pathogenic bacteria Infectious causes of cancer