History of Anti-Bacterial agents

There is evidence of antibacterial herbs or potions being used for many centuries. For example, the Chinese used moldy soybean curd to treat carbuncles, boils, and other infections. Greek physicians used wine, myrrh, and inorganic salts. In the Middle Ages, certain types of honey were used to prevent infections following arrow wounds. Of course in those days, there was no way of knowing that bacteria were the cause of these infections.

Bacteria are single-cell microorganisms first identified in the 1670s by van Leeuwenhoek, following his invention of the microscope. It was not until the nineteenth century, however, that their link with disease was appreciated. This followed the elegant experiments carried out by the French scientist Pasteur, who demonstrated that specific bacterial strains were crucial to fermentation and that these, and other, microorganisms were more widespread than was previously thought. The possibility that these microorganisms might be responsible for disease began to take hold.

An early advocate of a ‘germ theory of disease’ was the Edinburgh surgeon Lister. Despite the protests of several colleagues who took offence at the suggestion that they might be infecting their own patients, Lister introduced carbolic acid as an antiseptic and sterilizing agent for operating theatres and wards. The improvement in surgical survival rates was significant.

During the latter half of the nineteenth century, scientists such as Koch were able to identify the microorganisms responsible for diseases such as tuberculosis, cholera, and typhoid. Methods of vaccination were studied and research was carried out to try and find effective antibacterial agents or antibiotics. The scientist who can lay claim to be the father of chemotherapy—the use of chemicals against infection—was Paul Ehrlich. Ehrlich spent much of his career studying histology, then immunochemistry, and won a Nobel prize for his contributions to immunology. In 1904, however, he switched direction and entered a field which he defined as chemotherapy. Ehrlich’s principle of chemotherapy was that a chemical could directly interfere with the proliferation of microorganisms at concentrations tolerated by the host. This concept was popularly known as the magic bullet, where the chemical was seen as a bullet which could search out and destroy the invading microorganism without adversely affecting the host. The process is one of selective toxicity, where the chemical shows greater toxicity to the target microorganism than to the host cells. Such selectivity can be represented by a chemotherapeutic index, which compares the minimum effective dose of a drug with the maximum dose that can be tolerated by the host. This measure of selectivity was eventually replaced by the currently used therapeutic index.

By 1910, Ehrlich had successfully developed the first example of a purely synthetic antimicrobial drug. This was the arsenic-containing compound salvarsan. Although it was not effective against a wide range of bacterial infections, it did prove effective against the protozoal disease of sleeping sickness (trypanosomiasis) and the spirochete disease of syphilis. The drug was used until 1945 when it was replaced by penicillin.

Over the next 20 years, progress was made against a variety of protozoal diseases, but little progress was made in finding antibacterial agents until the introduction in 1934 of proflavine—a drug which was used during World War II against bacterial infections in deep surface wounds. Unfortunately, it was too toxic to be used against systemic bacterial infections (i.e. those carried in the bloodstream) and there was still an urgent need for agents which would fi ght these infections.

This need was answered in 1935 when it was discovered that a red dye called prontosil was effective against streptococcal infections in vivo . As discussed later, prontosil was recognized eventually as a prodrug for a new class of antibacterial agents—the sulpha drugs or sulphonamides. The discovery of these drugs was a real breakthrough, as they represented the first drugs to be effective against systemic bacterial infections. In fact, they were the only effective drugs until penicillin became available in the early 1940s.

Although penicillin was discovered in 1928, it was not until 1940 that effective means of isolating it were developed by Florey and Chain. Society was then rewarded with a drug which revolutionized the fight against bacterial infection and proved even more effective than the sulphonamides. Despite penicillin’s success, it was not effective against all types of infection and the need for new antibacterial agents still remained. Penicillin is an example of a toxic fungal metabolite that kills bacteria and allows the fungus to compete for nutrients. The realization that fungi might be a source for novel antibiotics spurred scientists into a huge investigation of microbial cultures from all round the globe.

In 1944, the antibiotic streptomycin was discovered from a systematic search of soil organisms. It extended the range of chemotherapy to the tubercle bacillus and a variety of Gram-negative bacteria. This compound was the first example of a series of antibiotics known as the aminoglycoside antibiotics. After World War II, the search continued leading to the discovery of chloramphenicol (1947), the peptide antibiotics (e.g. bacitracin , 1945), the tetracycline antibiotics (e.g.chlortetracycline , 1948), the macrolide antibiotics (e.g. erythromycin , 1952), the cyclic peptide antibiotics (e.g. valinomycin ), and the first example of a second major group of β-lactam antibiotics, cephalosporin C (1955).

As far as synthetic agents were concerned, isoniazid was found to be effective against human tuberculosis in 1952, and in 1962 nalidixic acid (the first of the quinolone antibacterial agents) was discovered. A second generation of this class of drugs was introduced in 1987 with ciprofloxacin.

Many antibacterial agents are now available and the vast majority of bacterial diseases have been brought under control (e.g. syphilis, tuberculosis, typhoid, bubonic plague, leprosy, diphtheria, gas gangrene, tetanus, and gonorrhoea). This represents a great achievement for medicinal chemistry and it is perhaps sobering to consider the hazards society faced in the days before penicillin. Septicaemia was a risk faced by mothers during childbirth and could lead to death. Ear infections were common, especially in children, and could lead to deafness. Pneumonia was a frequent cause of death in hospital wards. Tuberculosis was a major problem, requiring special isolation hospitals built away from populated centres. A simple cut or a wound could lead to severe infection requiring the amputation of a limb, while the threat of peritonitis lowered the success rates of surgical operations. This was in the 1930s—still within living memory for many. Perhaps those of us born since World War II take the success of antibacterial agents too much for granted.