History and curiosity.6

The use and abuse of alkaloids accompanies the history of mankind from the very beginning. Despite this fact, it is rare that individual natural products can be linked to distinct historical events with any degree of certainty. It seems, however, that the story of the red pigments produced by a restricted group of eubacteria and actinomycetes of the Serratia and Streptomyces genera constitutes an interesting exception to this rule. Such microorganisms are fairly ubiquitous and grow on many starch-rich culture media to form distinctive red colonies. Upon reaching maturity, these colonies may eventually become fluid and suspiciously resemble droplets of blood in their color, consistency, and shape. The historical literature is full of reports of the “bleeding” of bread and other foods. One of the oldest examples dates back to Alexander the Great's siege of Tyre in 322 B.C., when Macedonian soldiers noticed the appearance of blood inside a piece of bread. This was interpreted by the royal seers as a good omen that blood would be spilt throughout the besieged town, and was used to justify the horrible, but this time real, bloodshed that Alexander's troops subsequently inflicted on the inhabitants.

Numerous reports of bloodlike coloration in food in general and of “bleeding” communion wafers in particular were documented during the European Middle Ages. It may not come as a surprise that even the intellectual authorities at that time could not help but see miracles in such incidents, which seemed to provide physical evidence for the central dogma of transubstantiation occurring during the Eucharistic liturgy. The most famous case, referred to as the “Miracle of Bolsena”,5 occurred in 1263 in the Church of Saint Christina near Bolsena, a small town north of Rome. A priest, fighting against his loss of faith, was celebrating mass during a pilgrimage to Rome when he noticed blood dripping from the host. Pope Urban IV rapidly approved this miracle and declared that it should be commemorated as the festival of Corpus Christi, which is now an Integral part of the Christian calendar and still a public holiday in many Western European countries. This event in Bolsena led to the construction of the marvelous cathedral in close-by Orvieto in the then emerging Italian gothic style, where the relics of this miracle are kept as venerable religious treasures. Moreover, in 1508 Raphael chose this story as the subject of his famous fresco, the “Mass of Bolsena” decorating the papal apartments of Julius II in to hide the true motives behind the bloody pogroms committed by fanatical mobs (FIG.4).

Although one must concede that no rigorous proof can be made in retrospect that all of these historical events were caused by Serratia marcescens and its relatives, no other microorganism seems to produce colonies that more closely resemble drops of fresh blood. A case that occurred in northern Italy in 1819 is particularly noteworthy for various reasons, not least because it ultimately led to a great leap forward in microbiology in general. The repeated appearance of “bleeding” food in a village near Padova was labeled as witchcraft and led to a public frenzy. Three scientists independently and almost simultaneously helped to dispel the mist of superstition: the botanist Pietro Melo, the pharmacist Bartolomeo Bizio, and the physician Vincenzo Sette all recognized that fermentation was responsible for this event (although they argued with each other for the scientific priority). Although the causative germ was erroneously thought to be a fungus rather than a bacterium, these studies represent early examples of systematic microbiological investigations in the pre-Pasteur era. The investigators were able to show the transmission of the red color from one medium to another, they investigated the organism under the microscope, they demonstrated the role of humidity and temperature on its growth, and even performed some exploratory studies on the effect of certain chemicals (camphor, sulfur, tobacco smoke, etc.) on the growth of Serratia marcescens. Bizio coined the name ”Serratia” to honor Serafino Serrati (an Italian physicistis who built a streamboat at Forence before 1787) and added ”marcescens” after the Latin “to decay” because the pigment fades quickly, being sensitive to light. Although this name is now commonly used, many others were proposed in the following decades, some of which reflect the undisputable association of this microorganism with the historical and “prodigious” events referred to above (Micrococcus prodigiosus).

In the years after S. marcescens became the subject of many microbiological studies and even gained some popularity as a seemingly harmless object of classroom demonstrations. In 1906 a Dr. M.H. Gordon gargled in a culture of S. Marcescens and then recited passages of Shakespear to a House of Commons empty except for a scattering of agar dishes on the members’ benches. The bright-red colour showed that S. Marcescens had spread to the other side of the chamber from where Dr. Gordon had been standing. This was one of the earliest demonstrations that speaking, as well as coughing and sneezing, could project bacteria in to the air for large distances. In the late 1970’s, S. Marcescens attracted a new brand of notoriety when the US Army admitted having released it as a means of simulating germwarfare attacks in eight different parts of the country between 1950 and 1966. When details of the tests became public, the Pentagon announced that it had no evidence that they had led to any infections or deaths. It was only in the last decades that Serratia strains have been recognized as potentially hazardous pathogens, which can be implicated in ailments such as meningitis, osteomyelitis, pneumonia, sinusitis, wound infection, and urinary tract infections Patients with chronic debilitating disorders or in postoperative status are especially susceptible to infections by this opportunistic bacterium. The marked resistance of Serratia strains towards approved drugs undermines conventional therapy with standard antibiotics.

Prior to the development of synthetic colour chemistry, prodigiosin was produced commercially, albeit for a short time, for the dyeing of silk and wool.1

The history of prodigiosin and cancer began in 1891 with the studies of William B. Coley and the vaccine he invented. Dr. Coley combined the cultures of Streptococcus sp. and Bacillus prodigiosus (now called S. marcescens), and then sterilized them by either heat or filtration. The mixture was called the “Coley’s toxins”. This therapy was applied in the treatment of tumors with fascinating results in tumors of mesodermal origin. Although the biologically active substance in Coley’s toxins is described as tumour necrosis factor (TNF), a cytokine that is induced in response to lipopolysaccharide (LPS) and causes cancer cell death, prodigiosin might be contained in Coley’s toxin.7
Prodigiosin was first isolated from S. marcescens in pure form in 1929 by Wrede and Rothhass. Investigations during the 5 years after its isolation in pure form elucidated the main structural features and culminated in the assignment of structure I.(FIG.5) Beginning in 1957 several reports cast doubts on structure I, and the correct structure (FIG.1) was established in 1960 as a result of partial and total syntheses.8