ANTIBIOTICS

2010

ANTIBIOTICS are, strictly speaking, natural products secreted by microorganisms into their environment, where they inhibit the growth of competing microorganisms of different species. In common usage, the term is generally applied to a wide range of chemicals, whether directly isolated from mould ferments, their semisynthetic derivatives, or synthetic chemicals showing some structural similarities. Also, in everyday language the term is used to denote drugs with a selectively toxic action on bacteria or similar non-nucleated single-celled microorganisms (including chlamydia, rickettsia and mycoplasma), though such drugs have no effect on viruses. In this loose parlance even the sulphonamides may, incorrectly, be referred to as antibiotics because they are antimicrobial.

More confusing is the fact that a number of antibiotics are used as cytotoxic agents in cancer chemotherapy (e.g. bleomycin): see ANTICANCER AGENTS. Further, partly because of the recent development of high-throughput screens for lead chemicals, a number of new drug chemical classes have arisen from antibiotic leads (e.g. the CCK antagonist asperlicin and derivatives, from Aspergillus spp.).

The antimicrobial antibiotics have a selectively toxic action on invading bacteria, by virtue of exploiting differences in cellular characteristics between microorganisms and their human host cells. Major target sites are the bacterial cell wall located outside the cell membrane (animal cells have only a cell membrane), and the bacterial ribosome — the protein-synthesizing organelle within its cell — which is different between bacteria and animal cells. Viruses lack both cell walls and ribosomes and so are resistant to these and other similar antibiotics. A classification of therapeutically used antibiotics can be attempted on the basis of these mechanisms.

Antibiotics attacking the bacterial cell wall (by interfering with the synthesis of the bacterial cell wall peptidoglycan) include the beta-lactam antibiotics. These are comprised of the penicillin antibiotics (e.g. amoxycillin, ampicillin, methicillin) and the cephalosporin antibiotics (e.g. cefaclor, ceftazidime), together with newer synthetic classes such as the carbapenems (e.g. imipenem) and monobactams (e.g. aztreonam), which all share a common lactam-ring structure. Glycopeptide antibiotics (e.g. vancomycin, teicoplanin, ramoplanin, decaplanin) also inhibit cell wall synthesis. Polymixin antibiotics (e.g. polymixin B, colistin) have cationic detergent properties and disrupt the structure of the membrane by interaction with phospholipids. Bacitracin is a polypeptide antibiotic with an action similar to penicillin, but is too toxic to use systemically.

Examples of antibiotics that attack bacteria by inhibiting protein synthesis at the ribosomal level include the following; tetracycline antibiotics (e.g. chlortetracycline); aminoglycoside antibiotics (e.g. neomycin, streptomycin); macrolide antibiotics (e.g. erythromycin, clarithromycin. azithromycin); also chloramphenicol, fusidic acid and lincosamides (e.g. clindamycin).

Antibiotic-related agents that work by inhibiting DNA gyrase (topoisomerase II), the enzyme that maintains the helical twists of DNA, and are bactericidal, include the quinolones (e.g. nalidixic acid, ciprofloxacin, crosoxacin, cinoxacin, norfloxacin and ofloxacinall but the first-named are fluoroquinolones). Such agents are entirely synthetic.

Antifungal antibiotics include the polyene agent amphoterocin, which interferes with the permeability and transport of fungal membrane, allowing K+-loss; and is active systemically, but only against certain fungi and not bacteria. Nystatin is a polyene macrolide antibiotic used to treat fungal infections of the skin and gastrointestinal tract. Griseofulvin was isolated from cultures of Penicillium griseofulvum and was eventually developed as a narrow-spectrum antifungal with fungistatic properties, which works through a number of mechanisms, including impairment of microtubule function, and transport of material from cytoplasm to the periphery.

Anticancer antibiotics used in cancer chemotherapy are antimitotic cytotoxic agents (see ANTICANCER AGENTS) . These include the anthracycline antibiotics, doxorubicin, epirubicin, aclarubicin, idarubicin and mitozantrone (mitoxantrone, USA). Some metal-chelating glycopeptides can degrade DNA (e.g. bleomycin). Mitomycin is an alkylating agent acting against guanine. Dactinomycin is a Steptomyces antibiotic with a complex mode of action.

In conclusion, even with the proliferation of new antibiotics effective against specific types of target microorganisms, the biggest current problem with the continuing widespread use of antibiotics is the development of resistance to antibiotics that were formerly effective against them (e.g. MRSA — methicillin-resistant Staphylococcus aureus). One mechanism is by bacteria developing enzymes that degrade penicillins and some other β-lactams (see β-LACTAMASE INHIBITORS). Another problem is the occurrence of superinfections’ in which the use of a broad-spectrum antibiotic disturbs the normal, harmless, bacterial population in the body, as well as the pathogenic ones. In mild cases this may allow, for example, an existing but latent oral or vaginal thrush infection to become worse, or mild diarrhea to develop. In rare cases the superinfection that develops is more serious than the disorder for which the antibiotic was administered.