HEALTH AND MEDICAL PRODUCTS:TOPICALANTIBIOTICTR EATMENTS.

TOPICALANTIBIOTICTR EATMENTS

Antibiotics are typically described as antimicrobial agents of natural origin that are produced by microorganisms, which elicit a lethal or growth-inhibitory effect on a range of other types of microorganisms. These agents are molecules produced as secondary metabolites mainly by microorganisms inhabiting the soil, including molds and bacteria. In most cases, antibiotic production seems to be related to the sporulation process of the organismal life cycle. While many hundreds of different compounds possessing antibiotic activity have been identified from microorganisms since the early twentieth century, only a few compounds isolated have been shown to be both clinically therapeutic in the treatment of infectious disease and minimally toxic after administration. The modern under- standing of antibiotics as chemically therapeutic agents started with A. Fleming’s credited 1929 discovery of a fungal (common bread mold) metabolite from Penicilliumnotatum that demonstrated potent bactericidal effects. Termed penicillin, this antibiotic was not isolated and purified until the period of World War II (1939–1945), when two scientists,H. Florey and E. Chain, managed to produce penicillin on an industrial scale for widespread use. In addition, by the 1950s, several other antibiotics were in clinical use as the result of G. Domagk’s 1935 discovery of synthetic chemicals (sulfonamides) with broad antimicrobial activity, along with intensive research concerning other antimicrobial agents of natural origin. Three different antibiotics used in varying concentrations in present- day over-the-counter antibiotic treatments are neomycin, bacitracin, and polymyxin B. These antibiotics are usually formulated within chemically inactive creams or petrolatum-based ointments for topical application.

The range of bacteria or other microorganisms that are affected by a particular antibiotic is termed its spectrum of action. Broad-spectrum antibiotics are those that kill or inhibit a wide range of Gram-positive and Gram-negative bacteria, whereas narrow-spectrum antibiotics are mainly effective against either Gram-negative or Gram-positive bacteria. The Gram stain, named after its developer, C. Gram, is a laboratory staining technique that distinguishes between two groups of bacteria by the identification of differences in the structure of their cell walls. While the cell membrane is the critical barrier of the bacterial cell, separating the inside ribosome and nucleic acid components from the outside of the cell, the cell wall is a rigid structure outside the cell membrane that provides sup- port and protection. Although the cell walls of these bacteria are similar in chemical composition, Gram-positive bacteria remain colored after the staining procedure, whereas Gram-negative bacteria do not retain dye. The cell wall of Gram-negative bacteria consists of a thin layer positioned between an outer lipid-containing cell envelope and an inner cell membrane, whereas the Gram-positive cell wall is much thicker, lacks the cell envelope, and contains additional substances such as teichoic acid (poly- mers composed of glycerol or ribitol).

Many antibacterial agents produce a clinically beneficial effect by interfering with bacterial cell wall synthesis, cell membrane physiology, or protein synthesis. Peptidoglycan (and its synthesis pathway) is a major component of bacterial cell walls and thus one of the major targets of antibiotics in both Gram-negative and Gram-positive bacteria. Eukaryotic cells (cells that contain a true nucleus) within organisms such as humans lack cell walls and peptidoglycan. Other antibiotic compounds may target bacterial protein synthesis because bacterial ribosomes (termed 70S ribosomes) are different from the ribosomes (80S) of humans and other eukaryotic organisms. Thus, antibiotics may exert selective toxicity against bacterial pathogens without deleteriously affecting the consumer taking the antibiotic drug.

The actinomycetes are a large group of soil-inhabiting filamentous bacteria that produce many different chemical classes of antibiotics, including chemicals known as aminoglycosides. These compounds are water- soluble weak bases that are characterized by the presence of an aminocyclitol ring linked by glycosidic bonds to amino sugars in their structure. Within the actinomycetes, the species Streptomyces fradiae produces the broad-spectrum antibiotic neomycin, which causes the premature termination of protein synthesis (translation) in bacteria. Specifically, the ami- noglycosides irreversibly bind to the 30S subunit of the bacterial ribosome and interfere with the formation of the initiation complex to cause misreading of the mitochondrial RNA. First isolated by S. Waksman from a strain of S. fradiae in 1949, neomycin is mainly used topically in the treatment of skin and mucus membrane infections, wounds, and burns. Although used systemically in some cases, it is highly toxic. Neomycin sulfate, often used in topical antibiotic treatments in lieu of neomycin, is the sulfate salt of neomycin B and C, which are also produced by the growth of S. fradiae.

Endospore-forming Bacillus bacterial species produce a chemical class of antibiotics known as polypeptides, including bacitracin and polymyxin B. Polypeptide antibiotics consist of an amino acid chain. Bacitracin (C66H103N17O16S), a metal-dependent polypeptide complex of closely related analogues produced by common soil and water bacteria, including Bacillus subtilis and Bacillus licheniformis, is a narrow-spectrum antibiotic effective against Gram-positive bacteria. It prevents cell wall growth by inhibiting the release of the muropeptide monomer subunits of peptidoglycan from the undecaprenyl pyrophosphate lipid carrier mol- ecule that carries the subunit to the outside of the bacterial cell mem- brane. Binding to the undecaprenyl pyrophosphate lipid carrier impedes the dephosphorylation of the lipid carrier, which then obstructs the re- generation of undecaprenyl phosphate, thus preventing recycling of the bacterial transport system and the cell wall synthesis mechanism. Synthesis of teichoic acid, a key cell wall component in Gram-positive bacteria, which requires the same carrier molecule, is also inhibited. Bacitracin is limited to topical applications because it also interferes with sterol synthesis in mammalian cells by binding to pyrophosphate intermediates, thereby eliciting a toxic response when used systemically in humans.

Polymyxin B, a naturally occurring cyclic decapeptide produced by Bacillus polymyxa, is a narrow-spectrum antibiotic effective against Gram- negative bacteria and is usually limited to topical applications. It consists of a seven-member ring containing four diaminobutyric acid (Dab) resi- dues, one threonine residue, and a hydrophobic segment (i.e., dPhe-Leu and a linear amino-terminal region composed of three amino acids, Dab- Thr-Dab, together with an eight- or nine-carbon fatty acid [6-methyl heptanoic acid and octanoic acid, respectively] forming a long hydro- phobic tail). Considered one of the most efficient cell-permeabilizing compounds, it binds to membrane phospholipids within the cell membrane of the bacterium and thereby interferes with membrane physiological function. Polymyxin B acts a detergent, increasing the permeability of the membrane to cause the contents of the bacterial cell to leak out. Because of similarities in the phospholipid chemical composition of bac- terial and eukaryotic cell membranes, polymyxin B is rarely used as a systemic antibiotic treatment in humans, as it does not specifically target and destroy only bacterial cell membranes. Polymyxin B sulfate, frequently used in topical antibiotic treatments in lieu of polymyxin B, is the sulfate salt of polymyxin B1 and B2, which are also produced by the growth of B. polymyxa.

Topical antibiotic treatments typically also include a local anesthetic (numbing agent), such as pramoxine hydrochloride, that interferes with the function of nerves that sense pain.