Antibacterial agents

Antibacterial agents

The fight against bacterial infection is one of the great success stories of medicinal chemistry. During that latter half of the nineteenth century, scientists such as Koch were able to identify the microorganismsresponsible for diseases such as tuberculosis, cholera, and typhoid. Methods such as vaccination for fighting infections were studied. Research was also carried out to try and find effective antibacterial agents or antibiotics. However, 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. However, in 1904 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 which 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 proved effective against the protozoal disease sleeping sickness (trypanosomiasis), and the spirochaete disease of syphilis. The drug was used until 1945 when it was replaced by penicillin.

Over the next twenty years, progress was made against a variety of protozoal diseases, but little progress was made in finding antibacterial agents, until the introduction of proflavine in 1934. Proflavine is a yellow colored amino acridine structure which isparticularly effective against bacterial infections in deep surface wounds, and was used widely during the Second World War. It is an interesting drug since it targets bacterial DNA rather than protein. Despite the success of this drug, it was not effective against bacterial infections in the bloodstream and there was still an urgent need for agents which would fight these infections. This need was answered in 1935 with the discovery that a red dye called prontosil which was effective against Streptococci infections in vivo. Prontosil was eventually recognized asbeing a prodrug for a new class of antibacterial agents such as the sulfa drugs (sulfonamides). The discovery of these drugs was a real breakthrough, since they represented the first drugs to be effective against bacterial infections carried in the bloodstream. 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 sulfonamides. 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 chemical produced by a fungus to kill bacteria which might otherwise compete with it for nutrients. The realization that fungi might be a source for novel antibiotics spurred scientists into a huge investigation of microbial cultures, both known and unknown.

In 1944, the antibiotic streptomycin was discovered from a systematic search of soil organisms. It extended the range of chemotherapy to 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 the Second World War, the effort continued to find other novel antibiotic structures. This led tothe discovery of the peptide antibiotics (e.g. bacitracin (1945)), chloramphenicol (1947), the tetracycline antibiotics (e.g Chlortetracyc line (1948)), the macrolide antibiotics (e.g. erythromycin (1952)) and the cyclic peptide antibiotics (e.g. cycloserine (1955)). As far as synthetic agents were concerned, isoniazid (a pyridine hydrazide structure) was found to be effective against human tuberculosis in 1952, and in 1962 nalidixic acid the first 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, gonorrhea). This represents a great achievement for medicinal chemistry and it is perhaps sobering to consider the hazards which society faced in the days before penicillin.

Of the 12,000 antibiotics known in 1995, 55% were produced by filamentous bacteria (actinomycetes) of the genus Streptomyces, 11% from other actinomycetes, 12% from non filamentous bacteria and 22% from filamentous fungi (Berdy, 1995; Strohl, 1997).