Ureaplasma urealyticum (U. urealyticum)

Overview

Ureaplasma urealyticum is a wall-less bacterium in the class Mollicutes (phylum Mycoplasmatota)​. It belongs to the family Mycoplasmataceae (genus Ureaplasma)​. Two biovars now classified as separate species exist: U. parvum (biovar 1) and U. urealyticum (biovar 2)​. U. parvum is more common as a commensal, whereas U. urealyticum is somewhat more often linked to pathology (e.g. male urethritis and male infertility)​.^[1]Ureaplasma urealyticum is implicated in a spectrum of urogenital and perinatal conditions, chiefly as an opportunistic pathogen when it overgrows or invades new sites. Its role in disease is often linked to an increase in its numbers (or an unusual presence) relative to healthy states. Therapeutically, its vulnerabilities – acid intolerance, lack of a cell wall, and susceptibility to certain antibiotics – provide multiple angles to counteract its pathogenic effects in these conditions.

Habitat and Classification

U. urealyticum is typically a commensal opportunistic pathogen of the human urogenital tract. It colonizes the lower genital mucosa of healthy adults, often without symptoms​. In healthy conditions, it remains in low abundance and is kept in check by the normal flora. Transmission occurs via direct contact, or vertically from mother to neonate at birth​. Although frequently present in healthy individuals, it can cause disease when overgrown or introduced to normally sterile sites, and is therefore considered a pathobiont​. Immunocompromised hosts and disruption of the normal microbiota increase its pathogenic opportunities.

Morphology and Physiology

U. urealyticum is among the smallest free-living bacteria. Cells are pleomorphic and extremely small (approximately 100–800 nm in diameter), typically appearing as coccoid forms (clusters of tiny spheres)​. [2]^[x] They lack a cell wall entirely – only a single triple-layered unit membrane surrounds the cell​. This absence of peptidoglycan means they do not Gram stain (often described as Gram-negative by default)​. The membrane contains sterols, which Ureaplasma scavenges from the host, and this is required for growth​. U. urealyticum is non-motile (no flagella, though it may glide minimally) and non-spore-forming. ​It is a facultative anaerobe, able to grow in both aerobic and anaerobic environments, though it prefers microaerophilic conditions​. ^[3]

Metabolism

As a Mollicute with a drastically reduced genome, U. urealyticum has limited metabolic capacities and relies on the host for many nutrients. A defining biochemical feature is its urease activity – it hydrolyzes urea to ammonia and carbon dioxide. This not only provides a nitrogen source but also alkalinizes the local environment (ammonia elevates pH). In the acidic vaginal niche, this urease-driven ammonia production helps Ureaplasma survive by counteracting acidity, but it also produces a characteristic “fishy” odor in infections (ammonia contributing to the amine odor in bacterial vaginosis BV)​ U. urealyticum requires rich media (with serum for cholesterol, urea, and other growth factors) and parasitizes host resources like amino acids and fatty acids. It cannot synthesize many essential biomolecules, making it an obligate host-associated bacterium.

Virulence Factors

Ureaplasma urealyticum is a mucosal pathogen whose ability to cause disease stems primarily from a combination of colonization factors—such as adhesins like the Multiple Banded Antigen (MBA) that mediate attachment to host epithelium and facilitate immune evasion—and damage factors, including enzymes and proinflammatory lipoproteins that injure host tissues or dysregulate immune responses. While typically present at low abundance in the lower genital tract with limited pathogenicity, U. urealyticum can become harmful when bacterial loads increase or when the organism invades normally sterile sites such as the endometrium, placenta, neonatal lungs, or bloodstream. In these contexts, its virulence factors contribute to significant pathology, including chorioamnionitis, preterm labor, bronchopulmonary dysplasia, and disseminated infections in immunocompromised individuals.^[4] Unlike certain commensals, U. urealyticum provides no known benefits to the host—such as nutrient synthesis or pathogen exclusion—and is thus considered a parasitic member of the microbiome.^[5] The table below summarizes the major virulence factors contributing to its pathogenesis.

Virulence Factor	Description and Function

Urease

A nickel-dependent metalloenzyme that hydrolyzes urea into ammonia and CO₂. Urease functions in nutrient acquisition but also acts as a virulence factor. Ammonia is cytotoxic at high concentrations and elevates local pH, aiding Ureaplasma survival in acidic environments (e.g., vagina, urinary tract). This may enable ascending infections by overcoming acidic barriers. [6]

Multiple Banded Antigen (MBA)

A major surface lipoprotein present in multiple sizes (“bands”) that undergoes antigenic variation, allowing Ureaplasma to evade the host immune response by altering its surface epitopes. The C-terminal domain is highly immunogenic, eliciting host antibodies, but sequence variation permits immune evasion. This is a key mechanism contributing to chronic or recurrent infections. [7]

Phospholipases (A and C)

Enzymes that hydrolyze host cell membrane phospholipids, causing cell lysis and inflammation. This activity can degrade epithelial and chorioamnion membranes, contributing to tissue destruction. Released lipids may serve as nutrients for the bacterium.[8]

IgA Protease

An enzyme that cleaves secretory IgA, the main immunoglobulin in mucosal secretions. By degrading IgA, Ureaplasma reduces immune-mediated clearance on mucosal surfaces, facilitating persistent colonization of the urogenital tract.[9]

Surface Lipoproteins and Immune Activation

The membrane of Ureaplasma is rich in lipoproteins (e.g., MBA) that act as pathogen-associated molecular patterns, recognized by Toll-like receptors (especially TLR2). This recognition triggers a robust proinflammatory response (e.g., IL-6, IL-8), particularly in the amniotic fluid, leading to conditions like chorioamnionitis and preterm labor. In neonates, Ureaplasma colonization may cause bronchopulmonary dysplasia and is implicated in retinopathy of prematurity. While these molecules aid in adherence and persistence, they also provoke inflammation central to pathogenesis.[10]

Metallomics

Despite possessing one of the smallest genomes among self-replicating organisms, Ureaplasma urealyticum exhibits a highly specialized and tightly regulated dependence on certain trace metals, which are essential for its survival, metabolic activity, and pathogenic potential. The following table summarizes the organism’s trace metal dependencies, acquisition strategies, and interactions with host-imposed metal limitation, providing insight into its metallomic vulnerabilities and potential therapeutic targets.

Metal	Role in U. urealyticum Physiology and Pathogenesis
Nickel (Ni)	Nickel is an critical cofactor for urease, a major virulence factor. Urease hydrolyzes urea to ammonia and CO₂, aiding pH neutralization and tissue colonization. Genes for urease accessory proteins (UreE, UreF, UreG) support nickel incorporation. Some strains encode Nur (nickel-responsive regulator) and Ni transporters, suggesting active uptake. Nickel availability is critical—as Ni limitation impairs urease function, environmental stability, and virulence. [11][12]
Zinc (Zn)	Zinc is required for DNA-binding proteins and key enzymes (e.g., metalloproteases, polymerases). U. urealyticum encodes the Zur (zinc uptake regulator), indicating tight control of Zn homeostasis. Likely acquires Zn²⁺ via ABC-type or ZIP family transporters. Host Zn sequestration by proteins like calprotectin poses a nutritional challenge, prompting high-affinity Zn uptake responses. [13]
Manganese (Mn)	Functions in enzymes that substitute for iron (e.g., Mn-dependent superoxide dismutases). Regulated by the Mn-specific Mur regulator. Essential for managing oxidative stress and possibly metabolic processes. Like Zn, Mn is sequestered by host calprotectin, necessitating high-affinity Mn acquisition systems.[14]
Copper (Cu)	U. urealyticum is highly sensitive to copper. It lacks known Cu detoxification or efflux systems and is inhibited by Cu²⁺ concentrations as low as 30–60 μM. Copper toxicity can be exploited therapeutically; Cu chelators enhance killing. Host macrophages use copper for antimicrobial activity (e.g., in phagolysosomes), posing a significant threat to the bacterium. [15]
Iron (Fe)	U. urealyticum exhibits minimal iron dependence. It lacks genes for siderophores, heme biosynthesis, and other classical iron acquisition systems. A unique iron-independent ribonucleotide reductase allows DNA synthesis without iron. This adaptation enables survival under host-imposed iron limitation, achieving an “iron-free existence.” [16]

Vulnerabilities

Given its unique biology, U. urealyticum has several vulnerabilities that can be targeted to inhibit its growth or eliminate it. These weaknesses stem from its lack of certain structures, metabolic dependencies, and environmental sensitivities. U. urealyticum is vulnerable to environmental changes: low pH, high oxidative stress, and lack of available nutrients (cholesterol, amino acids, certain metals). It is highly drug-susceptible to antibiotics targeting protein or DNA synthesis, although intrinsic resistance to cell wall agents exists. Its fragility outside the host is a natural weakness that limits transmission mainly to close contact. These vulnerabilities guide both the body’s natural defenses and medical interventions to control Ureaplasma infections.

Vulnerability / Factor	Description and Therapeutic Implications

Acid Sensitivity

U. urealyticum thrives near neutral pH and is inhibited by acidic environments. Lactobacilli in the vagina maintain a low pH (~4.0–4.5), suppressing Ureaplasma overgrowth. When pH rises (e.g., in bacterial vaginosis), Ureaplasma can proliferate. Acidifying treatments such as boric acid or lactic acid gels, making vaginal acidity enhancement a natural and therapeutic defense.[17]

Metal Limitation

Host nutritional immunity limits access to essential metals like Zn and Ni. Calprotectin sequesters Zn and Mn, restricting growth. Nickel is a critical co-factor for urease activity; its limitation weakens acid resistance and colonization. Therapeutically, chelating agents targeting Ni or Zn such as clioquinol or dimethylglyoxime (DMG) reduce virulence factors and suppress Ureaplasma growth. Copper is also particularly toxic: U. urealyticum lacks robust Cu detox systems and is highly sensitive to Cu²⁺ stress. Copper ionophores have shown promising antimicrobial activity in vitro. [18]

Immune Factors and Microbial Competition

Lactobacillus species inhibit U. urealyticum via H₂O₂ production, low pH maintenance, and competition for epithelial adhesion. Ureaplasma is highly susceptible to hydrogen peroxide due to the absence of catalase. Probiotic restoration of Lactobacillus with vaginal microbiome transplant (VMT) may help suppress overgrowth. Innate immune components like defensins (cationic peptides) also target Ureaplasma’s membrane, and in immunocompetent individuals, Ureaplasma is typically maintained at low levels through these combined defenses.

Antibiotics

U. urealyticum is generally susceptible to protein synthesis inhibitors like tetracyclines (doxycycline) and macrolides (azithromycin), and to DNA-targeting fluoroquinolones. Resistance can arise via point mutations (e.g., in 23S rRNA, gyrA), but its small genome limits multidrug resistance. Strains resistant to one class often remain sensitive to another. Biovar 2 (U. urealyticum) tends to be more antibiotic-sensitive than U. parvum, offering a treatment advantage. [19]

Lack of Cell Wall

As a wall-less bacterium, U. urealyticum is highly sensitive to osmotic and physical stress. It cannot survive drying, hypotonic shock, or mild disinfectants. This fragility contributes to its host-restricted, mucosal niche and susceptibility to membrane-disrupting agents (e.g., polymyxins, digitonin, detergents).[20] While inherently resistant to β-lactams (no peptidoglycan target), it is vulnerable to membrane-destabilizing compounds, highlighting a potential Achilles heel outside the host.

Associated Conditions

The table below summarizes conditions and diseases associated with U. urealyticum, indicating whether its abundance is increased (implicated as a contributing pathogen) or decreased (protective role, which generally does not apply to this organism) in the condition. Also noted are possible therapeutic or preventive targets based on Ureaplasma’s vulnerabilities.

Condition	Role in Microbiome/Pathology
Non-Gonococcal Urethritis (NGU) (male)	Increased – U. urealyticum is a well-established cause of non-chlamydial, nongonococcal urethritis. It colonizes the male urethra and triggers inflammation, accounting for a significant fraction of NGU cases​emedicine.medscape.com.
Bacterial Vaginosis (BV)	Increased – Ureaplasma frequency and load are higher in BV, a dysbiosis state. It is often found co-existing with anaerobes in BV and may contribute to the altered vaginal environment​researchgate.net. (The overgrowth of U. urealyticum in BV is likely secondary to loss of Lactobacillus competition.)
Pelvic Inflammatory Disease (PID) (female reproductive tract infection)	Increased (co-infection) – U. urealyticum is sometimes isolated from the endometrium in PID patients, but its role is opportunistic. It may accompany other STD pathogens during upper genital tract infection. Studies show Ureaplasma can persist in the uterus during and after PID, but it doesn’t drastically alter PID clinical course​pmc.ncbi.nlm.nih.gov. Thus, it’s considered an adjunct pathogen rather than a primary PID cause.
Infertility (Male and Female)	Increased – Chronic Ureaplasma infection is associated with infertility. In women, persistent Ureaplasma in the cervix/uterus can cause endometritis or damage to fallopian tubes, hindering conception​pubmed.ncbi.nlm.nih.gov. In men, Ureaplasma in semen is linked to prostatitis or impaired sperm parameters (it can attach to sperm and reduce motility). While direct causation is still being studied, many infertile couples show higher prevalence of U. urealyticum infection.
Chorioamnionitis & Preterm Birth	Increased – Ureaplasma is the microbe most often isolated from infected placentas in preterm labor​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. It colonizes the chorioamnion and induces inflammation (chorioamnionitis); this intrauterine infection is strongly linked to preterm birth, especially in births <32 weeks​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. Ureaplasma infection in utero triggers cytokine release that can initiate labor​pubmed.ncbi.nlm.nih.gov. It is also associated with premature rupture of membranes.
Neonatal Chronic Lung Disease (Bronchopulmonary Dysplasia)	Increased – Colonization of preterm infants’ airways with U. urealyticum is a significant risk factor for bronchopulmonary dysplasia (BPD). Meta-analyses confirm that preterm babies who are Ureaplasma-positive (in respiratory specimens) have higher odds of developing BPD than those without Ureaplasma​pmc.ncbi.nlm.nih.gov. The organism likely persists in the immature lung, provoking prolonged inflammation that impairs lung development.
Retinopathy of Prematurity (ROP)	Increased (associated) – Emerging data suggest that inflammatory exposure to Ureaplasma in utero or postnatally may contribute to ROP, a retinal disease in preemies​pubmed.ncbi.nlm.nih.gov. Ureaplasma has been found in the respiratory tract of infants who later develop severe ROP more often than in those who do not. The hypothesis is that Ureaplasma-induced systemic inflammation (cytokines, etc.) affects retinal vascular development. This association is still under investigation, but is plausible given the known inflammatory role of Ureaplasma.
Urinary Calculi (Struvite Kidney Stones)	Increased – U. urealyticum is a urease-producing organism and has been implicated in infection-induced kidney stones. Urease raises urine pH and leads to crystallization of magnesium ammonium phosphate (struvite). Experiments show that inoculating Ureaplasma into animal bladders causes struvite stone formation in 80% of cases​pubmed.ncbi.nlm.nih.gov​pubmed.ncbi.nlm.nih.gov. Clinically, Ureaplasma has been cultured from the stones and urine of patients with struvite staghorn calculi, indicating it can be an etiologic agent of urinary stones (especially when standard cultures are negative for common urease bacteria like Proteus).
Postpartum Endometritis (post-childbirth uterine infection)	Increased – Ureaplasma urealyticum is frequently involved in postpartum endometritis, particularly after cesarean delivery or prolonged labor. It may ascend from the cervix to the uterus during delivery. Women with post-cesarean endometritis have significantly higher Ureaplasma loads in cervical cultures compared to those without infection (e.g., ≥10^5 CFU in 39% of endometritis cases vs 17% of controls)​pubmed.ncbi.nlm.nih.gov. Ureaplasma can cause persistent fever and inflammation despite standard antibiotics that don’t cover it.

Interventions

Intervention	Mechanism

Acetohydroxamic acid Pharmacological	Acetohydroxamic Acid (AHA), a urease inhibitor, functions as a microbiome-targeted intervention (MBTI) against Ureaplasma urealyticum by specifically disrupting its nickel-dependent metabolic pathway. AHA acts as a potent urease inhibitor by competitively binding to the nickel ions located at the active site of the urease enzyme—an essential virulence factor for U. urealyticum. This interference effectively prevents the pathogen from utilizing nickel to activate urease, thereby impairing its ability to hydrolyze urea into ammonia. By targeting the metallomic dependency of the pathogen, AHA directly modulates the microbial function and ecological fitness of U. urealyticum.
Antibiotics Pharmacological	Ureaplasma’s sensitivity to tetracyclines and macrolides. First-line therapy with doxycycline or azithromycin typically eradicates Ureaplasma. Beta-lactams are ineffective due to the absence of a cell wall.
Lactobacillus Probiotic	Restoration of acidic vaginal pH and normal flora can suppress Ureaplasma. Intravaginal lactic acid gels exploit its acid sensitivity. Probiotic Lactobacillus species further inhibit growth by producing bacteriocidins and hydrogen peroxide and occupying ecological niches.
Boric acid	Like Lactobacillus, boric acid can modulate the pH in the vagina.

Broad-spectrum coverage

Pelvic inflammatory disease (PID) regimens (e.g., ceftriaxone + doxycycline + metronidazole) include doxycycline to target Ureaplasma. Inclusion of tetracyclines ensures eradication even if Ureaplasma is not the primary pathogen.

Antibiotic sensitivity

Urease inhibition and pH management

Urease inhibitors (e.g., acetohydroxamic acid) limit stone formation by preventing ammonia-mediated alkalinization. Doxycycline can eradicate Ureaplasma from the urinary tract, and dietary or pharmacologic acidification may suppress recurrence.

Targeted antibiotic therapy

Screening and treating asymptomatic Ureaplasma infections, particularly in infertile couples, may improve reproductive outcomes. Doxycycline or azithromycin can reduce genital tract inflammation and improve sperm motility or endometrial receptivity.

Screening & macrolides

Macrolides (e.g., azithromycin) are preferred in pregnancy due to safety and efficacy. Early treatment of Ureaplasma colonization can reduce chorioamnionitis and associated preterm birth. Maintaining vaginal eubiosis also indirectly limits ascending Ureaplasma infection. (Source: onlinelibrary.wiley.com)

Inflammation control

In retinopathy of prematurity (ROP), maternal or neonatal treatment with macrolides may reduce systemic inflammation driven by Ureaplasma. Adjunct anti-inflammatory therapy could further mitigate retinal vascular dysregulation.

Add Ureaplasma coverage

In postpartum endometritis, routine antibiotic regimens may not eradicate Ureaplasma. Adding doxycycline leads to rapid symptom resolution by targeting its protein synthesis machinery. Guidelines recommend inclusion of tetracyclines to ensure mycoplasma coverage.

Acetohydroxamic acid

Administration of azithromycin to preterm infants colonized with Ureaplasma reduces the incidence of bronchopulmonary dysplasia (BPD). This strategy exploits the bacterium’s macrolide susceptibility and mitigates inflammation. (Source: fn.bmj.com)

References

1. Associations of Ureaplasma urealyticum infection with male infertility and intrauterine insemination outcomes.. Wan YY, Shi XY, Liu WJ, Bai S, Chen X, Li SY, Jiang XH, Wu LM, Zhang XS, Hua J.. (Asian J Androl. 2025.)
2. Ureaplasma gallorale sp. nov. from the Oropharynx of Chickens.. Koshimizu, K & Harasawa, Ryô & Pan, I.-J & Kotani, H & Ogata, M & Stephens, Edward & Barile, And.. (InternInternational Journal of Systematic Bacteriology.ational Journal of Systematic Bacteriology. 1987.)
3. BacDive in 2025: the core database for prokaryotic strain data.. Isabel Schober, Julia Koblitz, Joaquim Sardà Carbasse, Christian Ebeling, Marvin Leon Schmidt, Adam Podstawka, Rohit Gupta, Vinodh Ilangovan, Javad Chamanara, Jörg Overmann, Lorenz Christian Reimer. (Nucleic Acids Research. 2025.)
4. Placental Infection With Ureaplasma species Is Associated With Histologic Chorioamnionitis and Adverse Outcomes in Moderately Preterm and Late-Preterm Infants.. Sweeney EL, Kallapur SG, Gisslen T, Lambers DS, Chougnet CA, Stephenson SA, Jobe AH, Knox CL.. (J Infect Dis. 2016)
5. Ureaplasma: current perspectives.. Kokkayil P, Dhawan B.. (Indian J Med Microbiol. 2015.)
6. Ureaplasma: current perspectives.. Kokkayil P, Dhawan B.. (Indian J Med Microbiol. 2015.)
7. Ureaplasma: current perspectives.. Kokkayil P, Dhawan B.. (Indian J Med Microbiol. 2015.)
8. Ureaplasma: current perspectives.. Kokkayil P, Dhawan B.. (Indian J Med Microbiol. 2015.)
9. Ureaplasma: current perspectives.. Kokkayil P, Dhawan B.. (Indian J Med Microbiol. 2015.)
10. Ureaplasma: current perspectives.. Kokkayil P, Dhawan B.. (Indian J Med Microbiol. 2015.)
11. https://doi.org/.
12. Metal utilization in genome-reduced bacteria: Do human mycoplasmas rely on iron?. Perálvarez-Marín A, Baranowski E, Bierge P, Pich OQ, Lebrette H.. (Comput Struct Biotechnol J. 2021)
13. Metal utilization in genome-reduced bacteria: Do human mycoplasmas rely on iron?. Perálvarez-Marín A, Baranowski E, Bierge P, Pich OQ, Lebrette H.. (Comput Struct Biotechnol J. 2021)
14. Metal utilization in genome-reduced bacteria: Do human mycoplasmas rely on iron?. Perálvarez-Marín A, Baranowski E, Bierge P, Pich OQ, Lebrette H.. (Comput Struct Biotechnol J. 2021)
15. Differential Susceptibility of Mycoplasma and Ureaplasma Species to Compound-Enhanced Copper Toxicity. Totten AH, Crawford CL, Dalecki AG, Xiao L, Wolschendorf F, Atkinson TP.. (Front Microbiol. 2019)
16. Metal utilization in genome-reduced bacteria: Do human mycoplasmas rely on iron?. Perálvarez-Marín A, Baranowski E, Bierge P, Pich OQ, Lebrette H.. (Comput Struct Biotechnol J. 2021)
17. Ureaplasma urealyticum,. Sarah S. Long, Charles G. Prober, Marc Fischer.. (Principles and Practice of Pediatric Infectious Diseases (Fifth Edition), Elsevier, 2018)
18. Differential Susceptibility of Mycoplasma and Ureaplasma Species to Compound-Enhanced Copper Toxicity.. Totten AH, Crawford CL, Dalecki AG, Xiao L, Wolschendorf F, Atkinson TP.. (Front Microbiol. 2019)
19. Ureaplasma: current perspectives.. Kokkayil P, Dhawan B.. (Indian J Med Microbiol. 2015)
20. Localization of enzymes in Ureaplasma urealyticum (T-strain mycoplasma).. Masover GK, Razin S, Hayflick L.. (J Bacteriol. 1977)