Mobius Syndrome

In most studies, Möbius syndrome is defined as congenital facial weakness combined with abnormal ocular abduction. Möbius syndrome is due, in part, to the loss of function of motor cranial nerves (CNs). Most cases are diagnosed during infancy. The disease is not progressive. (See Etiology, Prognosis, Presentation, and Workup.)

Although von Graefe described a case of congenital facial diplegia in 1880,[1] the syndrome was reviewed and defined further by Paul Julius Möbius, a German neurologist, in 1888[2] and 1892.[3] Because of these contributions, Möbius is now the eponym used to describe the syndrome.

The definition and diagnostic criteria for Möbius syndrome vary among authors. Von Graefe and Möbius accepted only cases with congenital facial diplegia and bilateral abducens nerve palsies as constituting Möbius syndrome. In 1939, Henderson broadened the definition and included cases with congenital, unilateral facial palsy. (See Presentation and Workup.)[4]

Other authors are more restrictive in their definition, as a means of preventing the term Möbius syndrome from being assigned to conditions of a different pathogenesis. These investigators require the presence of a congenital musculoskeletal anomaly in order to make the diagnosis.

Congenital deformities

A striking feature in persons with Möbius syndrome is the high incidence of associated congenital deformities. The most common deformity is clubfoot. Brachial deformities and pectoral muscle hypoplasia have also been described. (See Presentation and Treatment.)

A congenital condition called the Poland sequence, characterized by ipsilateral hand malformations and by partial or complete absence of the pectoralis muscles and breast, is concurrent with Möbius syndrome in approximately 15% of patients.[5] (See Etiology and Presentation.)

Classification

In 1979, Towfighi et al proposed a classification system for Möbius syndrome based on pathologic differences observed in studies of patients with the syndrome.[6] The 4 proposed groups, which have no significant clinical correlations, are as follows:

• Group I - Simple hypoplasia or atrophy of CN nuclei

• Group II - Primary lesions in peripheral CNs

• Group III - Focal necrosis in brainstem nuclei

• Group IV - Primary myopathy with no central nervous system (CNS) or CN lesions

The etiology of Möbius syndrome remains controversial, but it appears to be multifactorial. Most investigators agree that in a subset of patients, the condition is predetermined genetically (approximately 2% of cases appear to have a genetic basis).[7] However, most cases are sporadic. Etiologic hypotheses include hypoxic/ischemic injury and intrauterine toxic exposure. By definition, traumatic injuries are not part of the Möbius syndrome.

Whether nerve, brainstem, or muscle aplasia is the primary event has not been established. Nerves that may be involved include CNs VI through XII, with general sparing of CN VIII. CN III and CN IV can be involved, but only rarely. The facial nerves (CN VII) are involved in all cases; the abducens nerves (CN VI), in a high percentage of cases (75%); and the hypoglossal nerves (CN XII), in only a minority of cases.

 

Mobius syndrome is a rare disorder. Only approximately 300 cases have been described in the English-language literature. The prevalence in the United States is reported as 0.002-0.0002% of births, or 1 case per 50,000 newborns.[7] In a nationwide Dutch survey reported in 2003, the prevalence of Möbius syndrome was at least 0.002% of births (4 cases per 189,000 newborns) for the years 1996–1998.[7] In 2007, the Möbius Syndrome Foundation estimated that 2000 individuals worldwide have the condition.[8]

Möbius syndrome is a static neurologic defect. Complications of Möbius syndrome depend on the severity of the patient’s deficits. They can include poor nutrition, dysphagia, aspiration pneumonia, and corneal ulceration/abrasion. In its mildest form, Möbius syndrome is not lethal.

In patients with severe brainstem compromise that causes dysphagia, aspiration, and an inability to protect the airway, death may occur at a young age.

Ear deformities have been described in patients with Möbius syndrome. In such cases, otitis media may complicate the patient's clinical course and require intervention.

In patients with Möbius syndrome, feeding problems at birth and in infancy may be severe and often are aggravated by associated micrognathia. In severe cases, death may occur in the perinatal period, often as a result of respiratory or bulbar problems. Life expectancy may be normal in patients with less extensive brainstem involvement.

In a British study, 8 of 29 patients with Möbius syndrome died over the course of 18 years. All deaths occurred shortly after birth. Four of the deaths were due to respiratory or bulbar problems.[9]

Parental education is required early in the child's life. Discuss airway compromise and the possible need for tracheotomy (if the condition is severe). Parents and patients also may require education concerning appliances that enable ambulation, if applicable.

The Moebius Syndrome Foundation states the following on its webpage: "The mission of the Möbius Syndrome Foundation is to provide information and support to individuals with Möbius syndrome and their families, promote greater awareness and understanding of Möbius syndrome, and to advocate for scientific research to advance the diagnosis and treatment of Möbius syndrome and its associated conditions." A great deal of useful information, as well as support group information, is available on the Web site.[10]

Numerous theories exist concerning the primary underlying pathogenesis of Möbius syndrome. Möbius himself believed that the condition was degenerative or toxic in origin and that it involved the nuclei of the affected nerves.[2, 3]

Some authors suggest that the underlying problem is an inherited congenital hypoplasia or agenesis of the CN nuclei.

Some view Möbius syndrome as a mesodermal dysplasia involving musculature derived from the first and second branchial arches. This theory holds that brainstem changes are secondary to retrograde atrophy of the CNs.

The close relationship embryologically between the motor nuclei of the sixth and seventh CNs explains the pathology of this congenital condition.[11]

Simultaneous limb malformations with CN dysfunction suggest a disruption of normal morphogenesis during a critical period in the development of the embryonic structures of these regions, most likely at 4–7 weeks’ gestation.

From a clinical point of view, regardless of the site of malformation, the result is absence of a functional neuromuscular system in the affected regions.[11]

Vascular interruption

Theories of vascular etiologies of the syndrome have many proponents. One such theory involves disruption of flow in the basilar artery or premature regression of the primitive trigeminal arteries. A second vascular theory is a disruption of the subclavian artery supply that involves interruption of the embryonic blood supply.

Genetics

The syndrome is listed as Online Mendelian Inheritance in Man (OMIM) Number 15700,[12]  with a gene map locus of 13q12.2-q13. A study found no microdeletions in this critical region and excluded several candidate genes.[13]  Scattered reports have described specific genetic localizations in Möbius syndrome. More reports will appear as the field of molecular biology expands. Genetic mapping, when available, will help in further defining the syndrome.

In 1977, Ziter et al reported a variant of Möbius syndrome co-segregating with a reciprocal translocation between chromosomes 1 and 13, ie, t(1p34;13q13), in at least 7 members of an affected family over 3 generations.[14]  In 1991, Slee et al described a girl aged 2.5 years with Möbius syndrome who had a deletion of band q12.2 on chromosome 13.[15]  The child's mother's karyotype was normal, but paternal chromosome studies were unavailable. (Her father had died.) Both reports suggested that a gene responsible for Möbius syndrome is located in region 13q12.2-q13.

In 1996, Kremer et al described a large pedigree with autosomal dominant Möbius syndrome consisting largely of asymmetrical, bilateral facial paresis. After exclusion of the candidate region on 13q12.2-13, they localized a gene to 3q21-22, raising the possibility of genetic heterogeneity of the syndrome.[16]

In 1997, Nishikawa et al reported a boy with a Möbius-like syndrome (ie, facial diplegia and ptosis but with normal extraocular movements and no skeletal anomalies) with a reciprocal translocation between chromosomes 1 and 2 (p22.3, q21.1).[17]

Familial cases are reported. In one family, affected siblings had facial diplegia, deafness, and mental retardation but no skeletal abnormalities. In another series, from 2 kindreds, more than 1 affected sibling had Möbius syndrome, but the nonconsanguineous parents were neurologically healthy.

A dominantly inherited syndrome (with the clinical features of Möbius syndrome and clubfoot, digital abnormalities, and arthrogryposis) was described in a family with 15 affected members in 2 generations.

Because of inconsistency in defining the condition, the role of inheritance in Möbius syndrome remains unclear. Pedigrees with autosomal dominant, autosomal recessive, and X-linked recessive inheritance patterns have been described. For this reason, providing genetic counseling to parents with an affected child remains difficult.

In facial diplegia without eye muscle involvement, the hereditary predisposition is greater, but recurrence depends on eliminating the known, genetically determined primary muscle or anterior horn cell disorders.

Baraitser stated that when the definition of the Möbius syndrome is restricted to the presence of CN VI and VII palsies (with or without bulbar involvement but with primary skeletal malformations), the risk to offspring of having the disease is low (2%).[9]

Toxins

In addition to genetic predisposition and vascular interruption hypotheses, evidence suggests a toxic origin for Möbius syndrome in some cases.

In a 1998 study of Brazilian infants, Pastuszak et al found a strong association between Möbius syndrome and prenatal use of misoprostol, a synthetic prostaglandin analog used to treat upper gastrointestinal ulceration.[18]  Misoprostol was self-administered by the mothers in Brazil as an abortifacient. Misoprostol is thought to cause an ischemic event in the embryonic brainstem early in gestation.

Exposure to ergotamine, which has vasoconstrictive properties, during early fetal development has been implicated in several cases of Möbius syndrome.[19]

In a 2005 case report, Puvabanditsin et al described an infant with Möbius syndrome associated with Poland anomaly that may have been related to ongoing maternal cocaine use during the first trimester of the pregnancy. The authors suggested that the cocaine exposure may have disrupted the fetal vascular supply.[20]

Kanemoto reported on the mother of an infant with Möbius syndrome who was treated with zonisamide during pregnancy for prepartum epilepsy. Since the teratogenicity of zonisamide has not been clearly defined, the authors were unable to exclude prenatal exposure to zonisamide as a possible cause of Möbius syndrome.[21]

Because of the early age at which Möbius syndrome becomes obvious, parents or other caretakers generally bring infant patients to medical attention. Facial and ocular symptoms are usually the presenting problems.[22]

Facial paralysis

Facial diplegia is the most noticeable symptom. This may be observed soon after birth, with incomplete eyelid closure during sleep, drooling, and difficulty sucking.[23] On occasion, the facial paralysis is not noticed for a few weeks or months, until the infant's inability to smile or the lack of facial movement with crying arouses the parents' concern.

Because of the patient’s facial and forehead immobility, the skin appears to be devoid of wrinkles. In some cases, only a slight diminution in the width of the palpebral fissures during sleep may be noted.

An inability to close the mouth is the rule. Undue prominence of the upper lip is a striking feature. In adults, the lower lip is usually everted and prominent. Food is apt to lodge in the cheeks when the patient eats.

Speech problems are reported in 76-90% of patients with Möbius syndrome.[24] Speech is usually indistinct because of the patient's inability to close his or her lips and make labial sounds. In some cases, speech impairment may be severe.

Hypogonadism

The association of Möbius syndrome with anosmia and hypogonadotrophic hypogonadism (Kallmann syndrome) or with hypogonadism alone has been reported.[25]

Autism

Möbius syndrome has been associated with autistic behavior. In 1989, Gillberg and Steffenburg reported that autistic symptoms are present in 30–40% of children and young adults with Möbius syndrome.[26] This has been confirmed in other series.[27]

Intelligence

The patient’s intelligence is usually normal, but mild mental retardation is thought to occur in approximately 10–15% of patients.[24] Many authors report that without formal testing, intelligence may be underestimated because of the patient’s facial appearance.

In a study involving extensive neuropsychological testing, Verzijl et al found no diminishment in intellect, attention span, or memory in 12 adults with Möbius syndrome, compared with the healthy population.[28] However, because none of the patients in the study had autism, these results could not be extrapolated to patients with a combination of Möbius syndrome and autism.

Other Abnormalities

Among the less common anomalies in Möbius syndrome are dextrocardia, arthrogryposis multiplex congenita, and the Klippel-Feil anomaly. A case of Möbius syndrome presenting with congenital bilateral vocal cord paralysis was reported by Kanemoto in 2007.[21]

Physical findings entirely depend on the case definition of Möbius syndrome. By using the most commonly accepted definition, the typical phenotypic appearance is an immobile facial appearance with various gaze palsies.

Facial nerve palsy is usually bilateral and incomplete, involving either the upper or the lower portion of the face. The resulting masklike face makes this diagnosis obvious upon initial inspection. The flattened facial expression, which deprives patients of the ability to convey emotions, causes patients to have difficulties in relating to other persons.

External ocular palsies, including ptosis, accompany the facial diplegia in approximately 80% of patients. These extraocular abnormalities may be single or multiple.

Secondary to the feebleness of blinking and the incomplete closure of the eyelids during sleep, the cornea and conjunctiva are poorly protected. Recurrent or chronic conjunctivitis frequently occurs. Corneal opacities are unusual but sometimes are observed in adults.

Bulbar weakness may be mild or severe. Dysphagia, caused by paresis of CNs IX and X, is common.

Skin abnormalities have been associated with the Möbius syndrome, including café-au-lait pigmentation, webbing of the axilla, and an absence of subcutaneous tissue.

Masticatory muscles are rarely affected. Instances of bilateral paresis of the soft palate and scattered instances of dysphagia (some of which resolve in infancy) have been reported. Infantile nasal regurgitation has been described in the literature.

In one study, the majority of 17 patients with Möbius syndrome had hearing in the normal range, with no consistent abnormal pattern present in the remaining patients.[29]

Abducens nerve palsies

Abducens nerve palsies are reported in approximately 75% of patients and are some of the most characteristic features of the syndrome. These palsies are characterized as follows in Möbius syndrome:

• Most are bilateral and usually complete

• Abducens paralysis is the only ocular palsy in approximately 50% of patients

• Affected children may be born with marked internal strabismus

• Ophthalmoplegia may be partial or complete

• Lateral gaze paralysis, which indicates medial longitudinal fascicular involvement, is often present

Hypoglossal nerve involvement

The hypoglossal nerve is the third most commonly affected cranial nerve (CN) and is involved in approximately 25% of reported cases.[23] Involvement of the hypoglossal nerves often leads to atrophy of the tongue. Patients may be unable to protrude their tongue beyond their lips because of this weakness. This involvement may result in paralysis and hypoplasia of the tongue, or fasciculations may be seen as a result of hypoglossal denervation. The ocular muscles are always involved when the tongue is affected.

Brachial malformation

Brachial malformation is common and can involve the following:

• It occasionally involves the arm, whereas the hand is always affected

• Reports include congenital amputation of the hand and clubhand

• In some cases, the affected hand is smaller than the other hand

• Syndactyly is not uncommon, and brachydactyly is frequently reported

• Other abnormalities in the upper extremities include finger webbing and an absence or hypoplasia of the radius, ulna, metacarpal, or phalanx

• Clubfoot, frequently bilateral, occurs in almost one third of patients; the deformity is usually correctable with surgery

Musculoskeletal abnormalities

Musculoskeletal abnormalities occur in one third or more of patients with Möbius syndrome. These anomalies may include the following:

• Talipes equinovarus

• Brachydactyly

• Syndactyly

• Congenital amputations (see the image below)

• Arthrogryposis

• Smallness of limbs

• Occasionally, hypoplasia or absence of the pectoralis major muscles (Poland anomaly)

  Autopsy photograph of a 3-month-old child with Möbius syndrome who died unexpectedly demonstrates congenital amputation of the left hand at the wrist.

The Poland anomaly, first associated with Möbius syndrome in 1973,[5] is generally unilateral and is associated with mammary hypoplasia of the same side.

An estimated 15% of patients with Möbius syndrome have missing truncal muscle groups, including the pectoralis or trapezius muscles. Other muscle groups that may be aplastic or hypoplastic include the latissimus dorsi, external abdominal muscles, serratus anterior, and intercostal muscles.

Orofacial abnormalities

Numerous orofacial abnormalities are present in Möbius syndrome. In several cases, the root of the nose has been described as broad and rather flat. Bilateral epicanthus has been reported, and scattered instances of ear deformities have been described (usually bilateral and confined to the lobe). An arched palate and a bifid uvula have been described, as have microglossia, microstomia, micrognathia, teeth and jaw malformations, and hypertelorism.

Complications include facial movement, speech difficulties, musculoskeletal and orthopedic manifestations, swallowing/feeding, visual tracking, and chronic conjunctivitis.  

No diagnostic laboratory studies yield findings specific to Möbius syndrome. Imaging studies—specifically, computed tomography (CT) scanning and magnetic resonance imaging (MRI)—may reveal calcifications in the regions of the CN VI nuclei and demonstrate cerebral malformations. Electromyography can be used to help determine whether a patient’s symptoms stem from birth trama and are therefore not associated with Möbius syndrome.

Some physicians do not pursue imaging studies of the brain, but many experts recommend them. CT scanning or MRI of the brain may demonstrate bilateral calcifications in the regions of the CN VI nuclei.[30] One report describes bilateral calcifications of the basal ganglia on the brain CT scans of 2 siblings with classic Möbius syndrome.[31] However, these calcifications are not specific for the disease.

It has also been found that, on imaging, the brainstem may appear hypoplastic, with straightening of the fourth ventricular floor. The absence or hypoplasia of CN VI and CN VII may be the most common radiologic features in sporadic Möbius syndrome, and hypoplasia of CN IX may be an associated feature.[32]

Brain MRI may help in determining whether other, perhaps genetically determined, cerebral malformations are present.

Although prenatal ultrasonography is not usually indicated, it has been used to depict basal ganglial and brainstem calcifications in the brains of developing infants.

Some instances of facial palsy occur with birth trauma, especially with the use of forceps in breech deliveries. By definition, traumatic injuries are not part of Möbius syndrome. Timing of the injury to the facial nerve may be important, and electromyography (EMG) can assist in this regard.

Denervation potentials are present only if the facial nuclei or nerves were injured 2-3 weeks or more before the electromyographic study. Facial muscles that are congenitally aplastic or hypoplastic as a result of Möbius syndrome or nerve injury occurring early in gestation do not demonstrate active denervation. This finding can help in differentiating Möbius syndrome from perinatal trauma to peripheral nerves.

In a study of 24 patients with Möbius syndrome, Cattaneo et al found 2 different, defined phenotypes after neurophysiological testing (which included EMG). Based on their EMG data, the authors postulated that the first group had rhombencephalic maldevelopment, while the second group seemed to have acquired a nervous system injury during intrauterine life.[33]

In a study of EMG results from 7 patients with Möbius syndrome, Jaradeh et al suggested that the primary cause of neural involvement was prenatal brainstem damage involving the motor nuclei and their internuclear connections.[34]

The diagnosis of Möbius syndrome soon after birth may be difficult. Möbius syndrome can easily be confused with congenital myopathies, muscular dystrophies, or congenital myotonic dystrophy. If abnormal, EMG findings can help in the differential diagnosis.

Few published cases contain pathologic descriptions. Gross findings include asymmetry of the medulla, but the external appearance of the brain generally is normal.

Upon histologic evaluation, the most notable abnormalities have been seen in the motor nuclei of the cranial nerves (CNs), especially in CN VI (see the first image below), CN VII, and CN XII and, to a lesser extent, in CN III and CN XI nuclei. CN VI often shows the most striking changes, with near-total neuronal loss and, sometimes, necrosis (see the second and third images below). The necrotic foci are round, well circumscribed, and basophilic. Degenerative periodic acid-Schiff–positive material may be seen.[6] The necrotic foci may be surrounded by radiating cell processes.

Gliosis may be seen in the affected regions, and occasional axonal spheroids have been seen in the periphery of the necrotic lesions. The pyramids may appear underdeveloped. Atrophy of the facial muscles has been described, with adipose and fibrous tissue replacement.

There are no laboratory studies that apply to the majority of Möbius syndrome cases.

Imaging studies are not necessary for the diagnosis of Möbius syndrome, but can be helpful to exclude other similar conditions.

Möbius syndrome is congenital and nonprogressive. No definitive treatment is available, with medical care being supportive and symptomatic.

Treatment for corneal ulcerations or abrasions may be required. These occur secondary to keratitis and conjunctivitis, which result from incomplete eyelid closure.

Congenital limb amputations or other musculoskeletal abnormalities may significantly compromise patients with Möbius syndrome. Splints, prostheses, or even prophylaxis for deep venous thrombosis may be indicated.

For a number of reasons, patients may be predisposed to infections. Brainstem abnormalities can predispose patients to aspiration pneumonia, which may be complicated by pulmonary infections. Vigilance and a low threshold for treatment are required. If the patient has structural anomalies of the ear, otitis media may complicate the patient's clinical course and require intervention.

Surgical therapy

Surgical care is symptomatic or cosmetic, but it is not curative of the underlying syndrome. Clubfoot, frequently bilateral, occurs in almost one third of patients. In most cases, the deformity can be corrected partially or entirely by means of orthopedic procedures.

Airway functions commonly are compromised. Tracheotomy may be required to support the airway and permit tracheobronchial clearing.

With the diffuse incidence of feeding problems in children with Möbius syndrome, supplemental energy intake via a feeding gastrostomy tube may be required. Nissen fundoplication procedures have not been helpful in treating neurogenic dysphagia and associated aspiration.

Most ophthalmologists recommend delaying surgery for strabismus because the condition frequently improves with age. Ocular surgical procedures have been successful in some patients with Möbius syndrome. In older patients, insertion of a gold weight into the eyelid may allow lid closure to protect the cornea.[35]

Consultations

Associated deficiencies in Möbius syndrome and its variants require a multidisciplinary approach by skilled specialists, such as the following:[25]

• Pediatricians

• General surgeons

• Pediatric dentists

• Orthopedic surgeons

• Ophthalmologists

• Pediatric otolaryngologists

• Psychologists

• Physiatrists

• Occupational and physical therapists

• Audiologists

• Speech therapists

Diet

If the brainstem is affected severely (enough to cause dysphagia), a dietician may assist with aspiration prevention.

Activity

Activity is not specifically limited in patients with Möbius syndrome, but it may be limited by the patient's physical abilities.

Recognition of the fact that affected regions have no functional neuromuscular system explains why nerve grafting, cross-face grafting, and cranial nerve (CN) substitution techniques have had poor success in animating the faces of patients with Möbius syndrome.[11]

However, reanimation procedures to counteract facial nerve paralysis that involve bringing in a new neuromuscular system may be successful, although the choice of donor nerves used to reinnervate the face may be limited by the extent of CN involvement in the patient's condition.[36] Restoration of function may be more successful if surgery is performed before age 7 years.

Functioning free muscle transplantation techniques have sometimes provided good results.[37]  Otolaryngologists and plastic surgeons have used the unaffected accessory nerve, crossed facial nerve branches, or the mesenteric branch of CN V as donors for reinnervation procedures. Other surgeons have designed living devices, composed of muscle and tendon transplants combined with reinnervation procedures, that have restored at least partial control of the facial musculature. Gracilis muscle transfer with masseteric nerve innervation is currently considered one of the best surgical options for the treatment of bilateral facial palsy.[36]  

Research into the psychological family dynamics of Möbius syndrome patients has drawn attention to the problems of parental bonding and possible disturbances of family dynamics. One contributing factor may be lack of feedback to the mother from the child, who may not be able to signal to her in the usual fashion by smiling or visual following.

When affected children reach an age of self-awareness, they realize that others notice their facial immobility. The incidence of behavioral problems is higher in patients with Möbius syndrome than in age-matched controls, and levels of caregiver stress and strain are also elevated.[38] Facial mobility may increase with age, and the condition may become less embarrassing than before, easing social interactions for the patient. A study providing data on quality of life did not show behavioral problems or reduced quality of life in children with Möbius syndrome, but results did indicate that children's emotional and social development should be closely monitored.{ref Family or individual counseling may prove helpful in these situations.[39]

Neuropsychological and intelligence testing are helpful in predicting and assisting possible learning deficiencies, autism, or various visual apraxias.

Follow-up care with the following therapies may be beneficial in patients with Möbius syndrome:

• Physical therapy - May be useful for managing congenital orthopedic problems or for postoperative care if orthopedic intervention is required

• Occupational therapy - May help patients, especially those without hands or digits, to accomplish activities of daily living

• Speech therapy - May be started if the deficits in the lower CNs are severe; severe facial nerve paralysis often mechanically affects speech

Consultations with orthopedists, physical therapists, occupational therapists, and speech therapists can be useful if indicated in the individual patient.

With few exceptions, pharmacologic intervention in patients with Möbius syndrome is used only for symptomatic treatment. As previously mentioned, patients with Möbius syndrome may be predisposed to infections, such as pulmonary infections resulting from aspiration pneumonia, and otitis media caused by structural anomalies of the ear. Vigilance and a low threshold for treatment are required. Antibiotics used in the treatment of infectious complications include amoxicillin and trimethoprim and sulfamethoxazole (TMP-SMZ).

Class Summary

Proper antibiotic therapy should be started in the event of infections such as pneumonia or otitis media.

Amoxicillin (Moxatag)

Amoxicillin is an ampicillin analogue with broad-spectrum bactericidal activity against many gram-positive and gram-negative organisms.

Trimethoprim and sulfamethoxazole (Bactrim, Bactrim DS, Septra DS)

TMP-SMZ is a synthetic, broad-spectrum antibacterial combination. It inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA), inhibiting bacterial growth.