The Origin, Etiology and Treatment of Syphilis ” And this disease of which I speak, this syphilis too will pass away and die out, but later it will be born again and be seen again by our grandchildren just as in bygone ages we must believe it was observed by our ancestors”. – Fracastoro, 1538 1 It has been written about, debated over, and has affected every culture it has come into contact with. One can only be amazed when examining the microscopic syphilis bacterium. It traveled the seas of 1492 with Columbus, fought alongside Hitler in the war of the worlds, and gambled with the likes of Al Capone. 2 This bacterium has been a part of hundreds of year’s worth of human history, and probably thousands of year’s worth of prehistory. Technology has enabled us to sequence the genome of syphilis, exposing every possible characteristic and genomic code function, yet no one knows where the bacterium calls home.

Syphilis has revolutionized western medicine and our approach to public health, yet no vaccine has been developed. It is a mystery how historical evidence has shown the symptoms of the disease since the beginning of mankind, yet outbreaks still occur in modern time. By understanding the theories of origin, the morphological, genomic, and relative characteristics of the disease and its treatment, the riddle of this disease may be cracked in the near future. Syphilis, the third most common sexually transmitted disease, affects 12 million new people each year and is the leading cause of stillbirths and deaths among newborns in many developing countries. 3 The causative agent of venereal syphilis is Treponema pallidum, under the Family Spirochaetaceae of the Order Spirochaeta les. It is a spirochete, a helical to sinusoidal bacterium ranging from 5 to 15 microns in length.

2 T. pallidum multiplies by binary transverse fission and enter the body through mucous membranes (squamous or columnar epithelium cells) or minor breaks or abrasions in the skin. From there, it migrates to every corner of the body through the blood and lymphatic circulatory system, infecting virtually every bodily organ, including the nervous system. Infections can even reach the womb, infecting the newborn known as congenital syphilis. 4 Despite its importance as an infectious agent, relatively little is known about T. pallidum in comparison with other bacteria. The genome of Treponema pallidum was sequenced in 1998 by the Institute for Genomic Research to show 1,138,006 base pairs with an average G + C content of 52.8%.

There are a total of 1,041 predicted open reading frames, with an average size of 1,023 base pairs, representing 92.9% of total genomic DNA. 5 Comparison of the T. pallidum genome sequence with that of another pathogenic spirochete, Borrelia, the agent of Lyme disease, identified unique and common genes and substantiates through considerable diversity observed among pathogenic spirochetes. Furthermore, the gene sequence has indicated that a Gap 1 sequence from T. pallidum is very closely related to GA PDH genes from the eukaryotic Euglenozoa, indicating that an inter kingdom gene transfer may have occurred between these organisms. 6 The sequencing of the Treponema pallidum genome can also set itself apart from many non-pathogenic relatives.

The first major difference is that syphilis has been hindered by the inability to culture the bacterium outside the human host. The reason for this is because scientists do not know the nutrition needed for the spirochete. 5 The second major difference revealed through gene sequencing is that the bacterium’s metabolism is very limited. Absent from the spirochete are many biosynthetic pathways. Examples include pathways for synthesis of enzyme co factors, fatty acids, nucleotides, and some electron transport proteins. Because of the limited biosynthetic capabilities, Treponema pallidum depends on the host for multiple nutrients.

Thus, the spirochete has a repertoire of transport proteins with broad substrate specificity to obtain the necessary nutrients from the environment. The transport protein code takes up a significant 5% of the T. pallidum genome. The genome encodes 18 distinct transporters specified for amino acids, carbohydrates, and cations. 5 The consequential use of many protein transporters is the necessity of an adequate amount of energy.

Contrasting from non-pathogenic relatives, Treponema pallidum lacks a TCA cycle. Rather, it uses carbohydrates such as glucose, galactose, maltose, and glycerol as an energy source. Phosphorylation within the T. pallidum is done by the usual enzyme. However, instead of the typical eu bacterial and kinase, T. pallidum contains homolog’s of these enzymes that use pyrophosphate. In T. pallidum, the kinase function is probably taken over by, which is capable of catalyzing formation by reversing its typical reaction. Obtaining inorganic phosphate is also different from other relatives in that the spirochete uses a sugar transport instead of an uptake system.

5 Differing in structure from the enteric Gram-negative bacteria, Treponema pallidum contains both outer and cytoplasmic membranes. Unlike the Gram-negative bacteria, the underlies the outer membrane and the mure in layer overlies the cytoplasmic membrane. This layer gives Treponema pallidum a unique characteristic different from other spirochetes because it has few proteins exposed on the surface. Many believe the surface genes undergo recombination in order to generate new surface proteins, permitting the organism to evade the human immune response. Analysis of T. pallidum indicates the presence of only 22 putative surface lipoproteins, as compared with 105 in B., consistent with results from ultra structural studies. 6 The outer proteins of T. pallidum are also different from other bacterium in that the repeat protein K, a specific protein for syphilis of unknown function that appear to be important in the immune response during syphilitic infection.

Experiments hint that repeat protein K give the bacterium an ability to evade the host immune responses and cause disease over a period of years to decades, hence the long latent and tertiary stages. 5 The motility of the spirochete also has unique characteristics not seen in other bacteria. In 1936, the active movement of venereal syphilis was studied by Dr. Wm. A. Hinton of Boston. It was during these studies that Dr. Hinton found a unique morphological property of the T. pallidum not seen in any other bacterium: the axial filament. Dr. Hinton observed that the motility of the T. Pallidum is somewhat characteristic and has been aptly described as that of an animated corkscrew. He noted that the organisms move chiefly in the direction of their long axis, trans versing a straight or an irregularly curved path with some rotary motion, as if they were actually screwing their way through the medium.

According to his research, a treponema may curve slowly or quickly, forming small or large arcs of circles, or it may bend so sharply in the middle as to form a right angle and then rather quickly resume its original straight corkscrew shape. 7 The axial filament is an internal flagella found only in the spirochetes. Axial filaments are composed of from 2 to over 100 axial fibrils (or endo flagella) that extend from both ends of the bacterium between the outer membrane and the cell wall, often overlapping in the center of the cell. A popular theory as to the mechanism behind spirochete motility presumes that as the endo flagella rotate in the peri plasmic space between the cytoplasmic membrane and the cell wall.

This could cause the corkscrew-shaped outer membrane of the spirochete to rotate and propel l the bacterium through the surrounding fluid. 2 The observed method explains how the bacterium can wiggle its way in and out of every cell and even invade host cells, which is known as intra cellularity. Intra cellularity can be achieved within thirty minutes after infection and can enter a variety of cell types including plasma cells, fibroblasts, macrophages, endothelial and epithelial cells, as well as additional bodily cells. 7 T. Pallidum can spread throughout the body within three weeks of infection, yet the disease is not highly contagious.

The rate of syphilis is 30%, meaning that there is a three out of ten chance of acquiring it from a single exposure to an infected sex partner. 2 This rate decreases as the disease progresses into different stages. Diagnosis of syphilis is through history, physical, dark-field, and examinations. The examination scans for motile or spirochetes within open lesions. Consequently, existing diagnostic tests for syphilis are suboptimal, and no vaccine against T. pallidum is available. 3 In an untreated adult, syphilis occurs in three recognizable stages.

The primary stage of the disease occurs 10-90 days after infection and is characterized by a chancre – a small, painless ulcer usually found on the genitals. The sore is teeming with spirochetes and is highly contagious. In this stage, the serological tests are positive in about 80% of the individuals. At the end of the primary stage, syphilis returns to the asymptomatic phase, neither causing nor exhibiting symptoms of the disease. This latency period lasts between six weeks to six months, until the secondary stage arises.

2 The secondary stage is characterized by a rash spreading from the palms and soles of the feet towards the trunk that may last 2-6 weeks. Other symptoms during this stage include mouth sores, enlarged lymph nodes, loss of hair, and inflammation of the eyes. Secondary syphilis is highly contagious through direct contact with the mucous membranes or other surfaces affected by the skin rash. During this stage, 100% of the individuals are serologically positive. After the secondary stage erupts, additional recrudescent eruptions may result over a span of 4-12 weeks. From the secondary stage, the disease returns again to an asymptomatic phase, a 10-12 year stage known as the latent stage.

2 During the latent stage, the infected person exhibits few or no symptoms of the disease and is not normally infectious. Early latency refers to the first four years when secondary relapses may occur; late latency is the asymptomatic period beyond four years. During this latter period, the patient harbors infectious organisms, especially in the spleen and lymph nodes and blood serology remains positive. 2 After 10-12 years, a tertiary stage develops in about 40% of untreated individuals with secondary syphilis. This stage is reached when the bacterium has invaded tissues throughout the entire body. It is characterized by large, tumor-like sores called gummas that form on the tissues of skin, muscle, digestive tract, liver, lungs, eyes, and nervous system.

Invasion of the bacteria into the central nervous system causes neuro syphilis, damaging the brain and spinal cord. 3 Sufferers develop partial or total paralysis, blindness, or even psychotic and unpredictable behavior. A delayed hypersensitivity response to the small numbers of treponemas in the lesions may be responsible for the development of gummatous disease. Though gummas sores can be external, people in the tertiary stage are not infectious, however about 4,000 die annually from tertiary syphilis in the United States. 2 Bejel, yaws, and pinta (collectively referred to as) are diseases closely related to syphilis that mainly occur in the tropics and subtropics. Unlike syphilis, they are transmitted by nonsexual skin contact-chiefly between children living in conditions of poor hygiene.

Like syphilis, these diseases begin with skin sores and have a latent period that is followed by more destructive disease. Bejel occurs mainly in the arid countries of the eastern Mediterranean region and West Africa while yaws occurs in humid equatorial countries. Pinta is common among Mexico, Central America, and South America. 8 Bejel, also known as endemic syphilis, is not transmitted sexually but via contact: for example hands to broken skin. The disease can also be spread by sharing eating utensils.

The causative agent of betel is T. Pallidum endemic um. 2 It commonly affects hygienically poor children ranging from 2-10 years of age. Depending on the route of transmission, skin or mucous membranes are the first to be infected but the bacterium can spread deeper into the bones. Stages of lesions can be observed in a primary and secondary stage. These papules, similar to the chancres of syphilis, are very infectious and form throughout the tissue of the body. 8 A third stage, called the latent stage, is similar to syphilis’s latent stage in that it lasts 5-15 years, spreading throughout the whole body during this time.

However, unlike syphilis, betel never attacks the nervous system, but instead attacks mainly the skin and skeletal systems. Late endemic syphilis can also develop highly destructive, deep gummas, caused by the same hypersensitivity seen in syphilis. Treatment of betel, which is completely curable, is similar to syphilis in using penicillin G or tetracycline. 8 Pinta, another non-venereal, treponema tous disease, is caused by T… This spirochete is morphologically indistinguishable from the organism that causes syphilis.

Meaning the Spanish word “painting”, pinta has an estimated 500,000 cases reported, affecting mainly young children. The transmission of this treponema tous disease is through human-to-human, nonsexual contact. Similar to betel and syphilis, pinta has infectious openings that appear within 2-6 months on initial infection. The infection is generally followed by a generalized eruption of flat, reddened areas, followed by the development of bluish coloration and a subsequent loss of pigmentation. 2 The main areas affected by pinta include the hands, feet, and scalp.

Unlike syphilis, the different stages of this disease are not clearly separated, and overlap of manifestations is common. T. is also curable by penicillin G. However, contrary to syphilis in which the lesions heal rapidly following antibiotic treatment, pinta lesions may require one year to fully resolve. 8 Yaws is another chronic treponema tous disease of poor hygiene. Yaws, also known as fame sia, is an infection of the skin caused by the spirochete Treponema. Similar to betel and pinta, yet unlike syphilis, yaws is contracted through human nonsexual contact. T. affect mostly children in Africa, South Asia and northern South America. Its highly contagious nature is indicated by an estimated 50 million cases worldwide. In endemic areas, 75% of the population contract yaws before reaching 20 years of age.

Similar to all three relatives, yaws forms infectious openings within months of infection. 2 The second stage of the disease begins 6-12 weeks after the initial infection when similar ulcerating lesions appear throughout the entire body. Infection of the soles and palms are characteristic in this stage, as they are in syphilis. Histopathology is also similar to that observed in syphilis, with minimal vascular changes and no endothelial cell proliferation. 8 Comparable to the tertiary stage of syphilis, the tertiary stage of yaws develops several years after the secondary stage if not treated, penetrating the body and causing destructive bone damage. The tertiary stage is harder to cure with penicillin, unlike the easily treated first and second stages due to resistance to antibiotics.

8 The debate about the origin of syphilis has continued for nearly 500 years. Clashing views based on biology, chronology, and paleontology differentiate the types of known theories. Syphilis was first recognized in Europe near the end of the fifteenth century, at a time where the venereal form would join the several forms of the endemic syphilis to cause the Europe-wide epidemic known as the ” gallic us” of the sixteenth century. 9 Traditionally, venereal syphilis was thought to have originated in the New World and was brought to Europe by Columbus and his crew in the 1490’s. 9 The lack of syphilitic evidence in the Old World prior to the 1500’s, in both skeletal remains and historical writings, supported this theory for many years. Today with recent finds, this view is being challenged.

There are now three main theories as to the origins of syphilis: Pre-Columbian, Post-Columbian, and the Unitarian theory. 9 The Pre-Columbian theory proposes that syphilis was present in Europe before Columbus’ voyage, but was not identified as a separate disease from leprosy before the 1490’s. 2 This theory states the types of that depended on direct skin contact were out competed by the hardier, sexually transmitted strain. Thus, the origin of venereal syphilis resulted from social and economic events and was not directly related to the return of Columbus from the New World.

A proponent of this theory was heavily supported based on the many references to “congenital” and “hereditary leprosy” in the European medical literature. Thirteenth-century references to ‘venereal leprosy’ may have indicated syphilis because leprosy is not sexually transmitted. In attempts to cure these “congenital” diseases, returning crusaders brought a ‘Saracen ointment’ containing mercury for treating ‘lepers,’ an appropriate medication for syphilis but not for leprosy. 9 The most argumentative proponent of this theory, however, is based on the archeological findings of Pre-Columbian bones affected by syphilis. 10 Archeologists are able to distinguish through bone characteristics of a skeleton if the person suffered from syphilis. For example, modifications to the shin and tibia are particular to syphilis.

Acquired syphilis of the bone occurs in the tertiary stage of the disease and involves the long tubular bones, the skull, and the vertebrae. The lesions include syphilitic osteochondritis, periostitis with extensive subperiosteal new-bone formation, and osteomyelitis, usually caused by the formation of gummas in the medullary cavity. 9 In a recent excavation, paleontologists exhumed the remains of a friary burial ground in Hull, England, dating back to the early thirteenth-century. The exhumation revealed 245 well preserved skeletons, 207 being relatively complete.

The scientists claimed that “no less than 60% of the skeletons showed evidence of syphilis”, most notably the characteristics in the fibula and tibia. 10 Charlotte Roberts of Bradford, a that studied the remains, has been a vital supporter of the Pre-Columbian theory and is considered one of the main representatives for the theory due to her significant findings. In the Hull findings, Dr. Roberts noted that the bones of three particular skeletons showed “evidence of localized disease of the thigh bones, saber-like thickening of shin bones, perforations of the palate, and erosion’s of the skulls frontal bone”. 9 This evidence took many scientists by surprise, especially when the carbon dating of the three skeletons dated back to between A.D. 1300-1450. If the deformed bones of the skeletons were indeed infected by syphilis, the carbon dating would indicate that syphilis was present in Europe roughly a century before Columbus’s voyage to the New World in 1492.10 Regardless of the significant evidence in this proposed theory, arguments tend to be made against it considering that most of the evidence is based on structural deformities.

Bruce Rothschild, a alongside Charlotte Roberts at the Hull excavation, believes a more prudent speculation off the arguments. Rothschild believes that the bone samples taken by Roberts were deformed because of. Known as “stone children”, is the calcification of a fetus or of fetal membranes. ‘The character of the pathology appeared to me to be calcified membranes / tissues, rather than periosteal reaction,’ he says. ‘The skull lesions are unlike those of treponema l disease (e. g., congenital syphilis) and the dramatic forearm calcification is unlike anything we have previously witnessed in over 500 cases of adult syphilis, nor in the periosteal reaction that characterizes yaws and betel — disorders in which children (though probably not fetuses) are frequently affected. ‘ 9 Rothschild has not found any evidence of syphilis in the Old World before Columbus, based on his study of 1,000 skeletons from Africa, the Middle East, Europe, and Asia.

If the Old World approach were correct, characteristic syphilitic bone lesions should have been found at anthropological dig sites in Egypt and Asia Minor. The notable absence of these lesions on recovered skeletal structures casts doubt upon this theory. Also, the Pre-Columbian theory does not explain why, if the disease has always been with us, there was the sudden epidemic in Europe of the 1400’s. Rothschild postulated in a popular, more traditional theory, known as the New World Origin, or the Post-Columbian theory.

9 The Post-Columbian theory proposes that Christopher Columbus and his crew contracted venereal syphilis as well as several forms of the endemic syphilis from natives on their first voyage in the West Indies in 1493.10 As the theory states, Columbus’s crew were infected during their visit in Haiti. About 40 men including Columbus sailed on the Santa Mar ” ia. Between 20 and 30 were on the Pinta and Ni~na each. Historical figures disagree on the exact number of men recruited, estimates range from 90 to 120 men on board the three ships, but only 87 names are known.

Most were Spanish, the largest number coming from around Palos; there was one Portuguese, one Genoese other than Columbus, one Venetian, and one Calabrian. 11 Upon returning to Europe, a majority of the crew joined the army of Charles V of France and participated in the siege of Naples. The town of Naples surrendered to the army on February 22nd, 1495 at 4: 00 P. M, on what is considered the “natal hour of syphilis”. The victory of the soldiers was followed by orgies which led to the infection of all participants, particularly of all soldiers, who then spread the disease on their journey back to France and Spain. Evidence suggests that Columbus himself died of syphilis infection. Derived from this is a possible explanation on how the disease reached epidemic proportions in the Mediterranean areas and Western Europe in such a short amount of time.

11 The traditional Post-Columbian theory is supported by evidence based on time and reasoning. The times of Columbus’ voyages and the outbreaks of syphilis in Europe are concurrent, lending credence to Rothschild’s claims. Rothschild argues that the syphilis epidemic could not have existed without Columbus’s journey. Support of Rothschild’s claims is apparent in the changes in clinical presentation, particularly in the first half of the 16th century. 9 Because the people of Europe had not been in contact with the condition before, the symptoms and signs of the disease were immediate, with no immunity to the disease. The rapid spreading of the disease finally slowed down due to the expanding influences of the Renaissance and practiced personal hygiene.

9 Rothschild’s view of the Post-Columbian theory was also supported by discovery of yaws in the New World. Rothschild believed that yaws mutated into the form of syphilis perhaps 1,600 years ago, and was waiting for Columbus and his crew. 9 Recently, however, the Post-Columbian theory has been attacked with such evidence as the bone excavations favoring the Pre-Columbian theory, as well as refuted on the ground of and clinical facts. Historical documents show that most of Columbus’s crew on the first trip rejoined the admiral in his second expedition as well, which left Europe on February 24th, 1494, and did not return until June 11, 1496. Few of Columbus’s crewmen arrived to Naples and those who did visited very shortly.

Based on these facts, an endemic of syphilis of such grave proportions could not have occurred. 11 This argument is supported by looking at the life cycle and contagiousness of syphilis. Once infected, the disease enters an incubation period that lasts up to three weeks. In addition, the rate of approximately 30% could not have infected as many hosts as the theory states. 2 Because of the Post-Columbian theory’s evidence of disproval, new theories have risen to incorporate the ideas of both theories, as well as the idea of gene mutation.

The Unitarian / Evolution theory, though similar to the Pre-Columbian theory, states that syphilis evolved independently on both continents and spread both eastward and westward. 10 This theory is defended by E.H. Hudson who suggests that there is only a single, presenting different clinical manifestations under different epidemiological conditions. He proposed that this form was the yaws that originated in central Africa. Hudson believes that the disease spread through Europe, Asia, and America through human migration as early as 100,000 years ago. Throughout the centuries, yaws spread throughout the valleys of the Tigris and Euphrates Rivers where it was referred to as betel. The spread of yaws ultimately led to European counties in the eighth-century when slave trading became conventional.

10 According to the theory, the cool, dry climate of Europe made it difficult for the disease to survive on dry skin. Thus yaws, favoring moist regions, migrated to the mouth, nostrils, anus, and genital area, causing what is known as non venereal syphilis. Unitarians believe that yaws adapted by migrating to different parts of the body, and also support Rothschild’s idea that yaws mutated into a more infectious, lethal organism of the sexually transmitted syphilis, known today as venereal syphilis. 10 Many scientists throw out these claims based on the fact that the Unitarian theory does not explain how syphilis reached epidemic proportions in such short amount of time.

The evolution of yaws presents another significant argument as well, based on the unlikely evidence suggesting yaws and syphilis were derived identically on different continents. 9 The deficiencies of the Unitarian, Old, and New World theories have led to the development of a fourth contemporary concept: the Modified Columbian theory. The theory proposes that “syphilis has always existed, but is only manifested in its catastrophic malignant form when a new strain of syphilis is introduced into a population not previously infected by that strain. This malignant period will sooner or later give way to a period of acclimation and less virulent forms of the disease, until such time as another novel strain of syphilis arrives”.

12 Over time human bodies can become acclimated to the syphilis disease, though not entirely immune to it. It is a process which can take decades or centuries, but equilibrium between the body and the bacterium can be achieved. While undisturbed, this period of balance will see mostly minor manifestations of syphilis. In contrast to this, if syphilis is introduced into a population of individuals who have not been previously infected, the disease will appear in its worst form possible: malignant syphilis.

In this form, the disease rampages through the body in an unpredictable and lethal manner. 12 Syphilis had most likely visited Europe long before the 1400’s but, given time, the inhabitants became acclimated to the particular strain of the bacterium. Regardless of the adaptation, it did not guarantee their safety against the new strain of syphilis Columbus brought back from Haiti. Thus, the inhabitants had no immunity to the new strain as it spread rapidly throughout Europe. This was the basis for the epidemic of the 1500’s. 9 The Modified Columbian Theory takes into perspective a sum of ideas found in all three main theories, and has the most evidential support.

The Modified Columbian Theory is able to answer for the origination of syphilis, its migratory patterns, the different types of strains, and the cause for the European epidemic of the fifteenth century. Because of the epidemic, partial treatments for syphilis, such as mercury, were used. But it was not until the twentieth-century before the first successful treatment was discovered. 12 Determining T. pallidum’s susceptibility to antibiotics was a slow and difficult process, mainly because of an inability to cultivate the organism using standard micro biologic techniques. A significant step in the treatment history began in 1905 when Fritz Schaudinn and Erich Hoffmann discovered the causative bacterium. Subsequently, in 1906, German bacteriologist August von Wassermann developed the first blood reaction test for the disease’s diagnosis.

These two discoveries soon paved the way for a new era in disease treatment. The modern era of chemotherapy began with the work of German physician Paul Ehrlich (1854-1915). 2 While considering the phenomenon of differential staining of different bacteria and of different components of eukaryotic cells, he speculated that if a dye chemical could bind to one cell and not another or to one substance within a cell and not others, perhaps chemicals could selectively kill certain pathogens without harming the surrounding host cells. 2 The proposal, coined a “magic bullet”, would work selectively on the bacteria that caused it without destroying the host. His speculation paid off in 1904 when he discovered that the use of a try pan red dye was active against the trypanosome that caused African sleeping sickness. Following the discovery, Ehrlich and his partner Saha chiro Hata found the compound to be active against syphilis spirochete.

Ehrlich dubbed the compound Salvarsan. 2 Though relapses were common, and treatments were expensive and painful, Salvarsan, along with mercury and bismuth ointments, were the only options available for syphilis treatment at that time. The era of chemotherapy ultimately led to the age of antibiotics with the discovery of penicillin. In 1929, Alexander Fleming discovered the anti-bacterial qualities of the mold penicillin.

2 Ten years later, Howard Florey and Ernst Chain took up Fleming’s research and found a way to purify penicillin, making it safe and effective for use in humans. 2 After 1945 penicillin became widely available and accepted as the treatment of choice for syphilis. The antibiotic was introduced in a time when less than one out of every one hundred patients recovered from syphilis. Penicillin is still used today to treat syphilis in an inject able form called penicillin or penicillin G. 2 How does penicillin inhibit bacterial growth? In 1965, James Park and Jack Strom inger deduced that penicillin blocks the last step in the cross linking of different strains. 3 They proposed that penicillin inhibits the enzyme catalyzing the reaction, thus resulting in osmotic lysis due to poorly linked chains.

Different antibiotics attack the enzymes of synthesis at different stages. A detailed overview of synthesis can show which antibiotics affect which enzymes in synthesis. 3 The biosynthesis of consists of three stages, each of which occurs at a different site in the cell. Stage 1 occurs in the cytoplasm.

In this stage N- and N-acetyl- are synthesized in the form of their uracil di phosphate derivatives. ATP energy is used to make the peptide bonds on the chain. The only antibiotic that affects this stage of cell wall metabolism is D-. D- is a structural analog of D-alanine; it binds to the substrate binding site of two enzymes inhibiting both D-Ala racemose and D-Ala-D-Ala, thus being extremely effective in preventing D-alanine from being incorporated into the N-.

2 Stage 2 of synthesis occurs on the inner surface of the cytoplasmic membrane where N- is transferred from UDP to a phosphate carrier. From here, it is modified to form the repeat subunit. The nature of the modification depends upon the organism. The last part of stage 2 is signaled by the translocation of the completed subunit to the exterior of the cytoplasmic membrane. The only antibiotic that affects this stage of cell wall synthesis is bacitracin. Bacitracin is an inhibitor of the lipid phosphatase.

2 Stage 3 occurs in the peri plasmic space and in the growing of the cell wall. The carrier returns to the membrane, obtaining a phosphate and enabling the carrier to accept other N-acetyl-. The earliest antibiotics of this stage are and. They act by binding to the D — D-alanine peptide termini of the carrier. This inhibits the enzyme. The stage continues with – the binding of soluble uncross linked to the preexisting, cross linked cell wall matrix.

Penicillin is a structural analog of the D — D-alanine end of the strand. The penicillin cell wall consists of as many as seven enzymes (depending on the bacterial species) which bind units via their D — D-alanine residues. The most crucial feature of penicillin is the ss-lactam ring. The ss-lactam’s fill these substrate binding sites and thus prevent the binding of D — D-alanine residues. Recently, however, additional mechanisms have been suggested on the action of penicillin’s on bacteria. It has been discovered that bind to several penicillin-binding proteins and may destroy bacteria by activating their own auto lytic enzymes.

Other mechanisms of action include stimulating special proteins called bacterial holies to form holes or lesions in the bacterial plasma membrane. Because of the complexity of the actions of penicillin, the mechanism is not completely known. 2 Early and later stages of syphilis can be treated by penicillin G; however the later stages require larger doses over a longer period of time. For example, in neuro syphilis cases, treponemas occasionally survive such drug treatments. 2 Immunity to syphilis is usually never reached, and subsequent infections can occur even when the initial infection has been treated by antibiotics.

If syphilis is able to develop or acquire resistance to an antibiotic, then that substance becomes useless in the treatment of the infectious disease caused by that pathogen (unless the resistance can somehow be overcome with secondary measures). So as pathogens develop resistance, humanity must find new antibiotics to fill the place of the old ones in treatment regimes. 3 Today, syphilis remains a worthy target for biomedical research. Modern approaches to understanding the origin and etiology of syphilis provide the background for promising breakthrough discoveries. Though gene sequencing has shed light of genetic promiscuity for the disease, over 40% of the genome has functions that are still unknown. Because there are still unanswered questions about the spirochete, prevention is the key to controlling the disease.

Methods such as public education, improved sexual hygiene, condom usage, and immediate infection control could halt the rising incidences of syphilis around the world. These approaches, with the advanced technology of tomorrow, may make the modern medical ideal of a “magic bullet” possible to achieve.


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