History

The first scientific recording of antibiotic activity was made by Louis Pasteur, who in 1877 reported that animals injected with an inoculation containing Bacillus anthracis and certain other common bacilli failed to develop anthrax.

In 1881, Tyndal in his Essays on the Floating Matter of the Air in Relation to Putrefaction and Infection reported that in some tubes containing a nutritive infusion and bacteria which had become contaminated also with Penicillium glaucum, the bacteria lost their ‘transilatory power and fell to the bottom of the tube’. Tyndal attributed this phenomenon to the cutting off of the oxygen supply to the bacteria by the pellicles formed by the mould. Ten years after Pasteur’s discovery, Emmerich (1887) accidentally discovered that a guinea-pig which had previously been injected with Streptococcus erysipelatis failed to develop cholera when injected with virulent cultures of Vibrio cholerae. He immediately recognized the significance of the discovery and was able to prevent anthrax in experimental animals by administering S. erysipelatis prior to the injection of B. anthracis.

Bouchard (1889) noticed that Pseudomonas aeruginosa prevented the development of anthrax in the rabbit; this observation was extended in scope by Woodhead and Wood (1889), who found that sterilized cultures of P. aeruginosa exerted the same protective effect against anthrax. The lytic action of certain Actinomycetes on various microorganisms was observed by Brunel. Emmerich with his colleague Low further studied the protective action of culture filtrates of P. aeruginosa; they concentrated these cell-free filtrates to 1/10th of their original volume and demonstrated that they destroyed Corynebacterium diphtheriae, staphylococci, streptococci, the pneumococcus, the gonococcus, Vibrio cholerae and Shigella paradysenteria in vitro. The active principle present in this preparation has now been isolated and purified and its structure determined. The recognition of the phenomenon of antibiosis had now been established but in 1928 Fleming noted the inhibition of bacteria by a colony of Penicillium notatum that had developed as a contaminant on a Petri dish. He advocated in his paper (Fleming, 1929) the possible clinical use of the substance formed by the Penicillium culture.

The advent of World War II launched a large-scale programme for the production and testing of the substance now known as penicillin, andthe resources of industry and academic institutions were devoted to the study of this substance and the search for other antibiotics. This led to the discovery of streptomycin, aureomycin, chloromycetin and many other antibiotics involving notably various species of Streptomyces. High-yielding strains of Penicillium chrysogenum which produce little pigment have now replaced P. notatum for penicillin manufacture. Preferential synthesis of benzylpenicillin is achieved by the addition of phenylacetic acid to the fermentation medium.

Clinical use

Of the antibiotics in clinical use, most are of bacterial or fungal origin (Table 30.1). Among the bacteria, the genus Streptomycesis particularly noteworthy, as it produces antibiotics such as streptomycin, chloramphenicol, chlortetracycline, tetracycline, erythromycin and neomycin. The penicillins, griseofulvin (an antifungal agent) and cephalosporins are of fungal origin.

Table 30.1 Some clinically important antibiotics

The cephalosporins (cefalosporins) are broad-spectrum antibiotics related both structurally and clinically to the penicillins. Being stable in acid solutions, some can be administered orally. Cephalosporin C arises by fermentation utilizing Cephalosporium acrimonium. As shown in Fig. 30.1, cephalosporin possesses two side-chains and substitution of these with a variety of groups has given rise to a considerable number of clinically effective drugs; some twelve, with theirpreparations, are listed in the current British National Formulary. They are usually graded, somewhat arbitrarily into first-, second- and third-generation cephalosporins, which roughly conform to the dates they were introduced and the particular type of derivative. Drugs from all generations are currently in use.

Fig. 30.1 Structures of some antibiotics

Other antibiotics of bacterial origin are the actinomycin, bacitracin, tyrothrycin and polymixin groups. These are all polypeptides and although their strong antibacterial properties were recognized early in the development of antibiotics their cytotoxicity prevented clinical use as internal medicines. However, the subsequent quest for anticancer agents led to a renewed interest in their antitumour action and now some of them (e.g. doxorubicin, daunorubicin, actinomycin D) are used to treat a variety of cancers. Such cytotoxic antibiotics can completely block RNA replication and are among the most potent antitumour compounds discovered but, like others of this group, cause unwanted side-effects owing to their non-selective action.

Unfortunately, due in part to the widespread and often indiscriminate use of antibiotics, together with poor hygiene, many pathogenic organisms have acquired a resistance to specific antibiotic treatments and these strains are particularly evident in the hospital environment. The problem is further compounded by the fact that resistance to a particular antibiotic can be transferred from one organism to another (jumping genes). Thus, the clinician’s antibiotic armamentarum is being steadily eroded and research directed towards the isolation or synthesis of new drugs is still a matter of considerable urgency.

Antibiotics are employed topically, orally or as injections but in order to reduce the development of antibiotic-resistant strains of microorganisms, they are now being prescribed in a more restrictive manner than was originally the case. For this reason the use of topicalcreams and ointments has declined although topical ocular preparations remain important.

The varied chemical nature of a number of antibiotics is illustrated in Fig. 30.1.

Lichens

Many of these appear to owe their bacteriostatic and antifungal properties to usnic acid or vulpinic acid.

Order Coniferae

Various essential oils from Juniperus and Pinus spp. have antibacterial activity.

Monocotyledons

Fresh garlic owes its antibiotic action to alliine, a sulphur-containing amino acid; ginger has antibacterial properties, so too aloe vera gel.

Dicotyledons

Examples from this group are: the sesquiterpene ketones of hops (humulene and lupulene) and those of myrrh (furanodiene-6-one and methoxyfuranoguaia-9-ene-8-one); protoanemonine, a lactone present in Anemone pulsatilla and many other Ranunculaceae; various sulphur-containing compounds found in the Cruciferae; plumbagin (2-methyl-5-hydroxyl-1,4-napthaquinone), found in Drosera; and compounds found in compositous plants such as burdock, thistle and Hieracium pilosella. The last plant, mouse-ear hawkweed, has been used clinically for the treatment of Malta fever. Mastic gum is effective in the treatment of gastric ulcers and has been shown to be active in low doses against Helicobacter pylori, an organism associated with this condition, (F. U. Huwez et al., New Engl. J. Med., 1998, 339, 1946). Cinnamon extracts have been shown to inhibit the growth and urease activity of the same organism (M. Tabek et al., J. Ethnopharm, 1999, 67, 269). Many other plants have been screened for antimicrobial activity and new reports continually appear in the literature.

Marine organisms

Cephalosporium acremonium—see above. The marine streptomycete, Streptomyces tenjimariensis produces istamycin A and B, active against Gram-negative and Gram-positive bacteria.

Plants/insects

Propolis (bee glue) prepared by bees from the pollen of various species of tree (q.v.) has bacteriostatic activity irrespective of geographical source.