Among the most powerful bactericidal antibiotics are those that possess a polypeptide structure. Many of them have been isolated, but unfortunately, their clinical use has been limited by their undesirable side reactions, particularly renal toxicity. Another limitation is the lack of systemic activity of most peptides following oral administration. A chief source of the medicinally important members of this class has been Bacillus spp. The antitubercular antibiotics capre-omycin and viomycin (see Chapter 6) and the antitumor antibiotics actinomycin and bleomycin are peptides isolated from Streptomyces spp. The glycopeptide antibiotic vancomycin, which has become the most important member of this class, is isolated from a closely related actinomycete, Amycolatopsis orientalis.
Polypeptide antibiotics variously possess several interesting and often unique characteristics: (a) they frequently consist of several structurally similar but chemically distinct entities isolated from a single source; (b) most of them are cyclic, with a few exceptions (e.g., the gramicidins); (c) they frequently contain d-amino acids and/or "unnatural" amino acids not found in higher plants or animals; and (d) many of them contain non-amino acid moieties, such as heterocycles, fatty acids, sugars, etc. Polypeptide antibiotics may be acidic, basic, zwitterionic, or neutral depending on the number of free carboxyl and amino or guanidino groups in their structures. Initially, it was assumed that neutral compounds, such as the gramicidins, possessed cyclopeptide structures. Later, the gramicidins were determined to be linear, and the neutrality was shown to be because of a combination of the formylation of the terminal amino group and the ethanolamine amidation of the terminal carboxyl group.230
Antibiotics of the polypeptide class differ widely in their mechanisms of action and antimicrobial properties. Bacitracin and vancomycin interfere with bacterial cell wall synthesis and are effective only against Gram-positive bacteria. Neither antibiotic apparently can penetrate the outer envelope of Gram-negative bacteria. Both the gramicidins and the polymyxins interfere with cell membrane functions in bacteria. However, the gramicidins are effective primarily against Gram-positive bacteria, whereas the polymyxins are effective only against Gram-negative species. Gramicidins are neutral compounds that are largely incapable of penetrating the outer envelope of Gram-negative bacteria. Polymyxins are highly basic compounds that penetrate the outer membrane of Gram-negative bacteria through porin channels to act on the inner cell membrane.231 The much thicker cell wall of Gram-positive bacteria apparently bars penetration by the polymyxins.
The isolation of the glycopeptide antibiotic vancomycin (Vancocin, Vancoled) from Streptomyces orientalis (renamed A. orientalis) was described in 1956 by McCormick et al.232 The organism originally was obtained from cultures of an Indonesian soil sample and subsequently has been obtained from Indian soil. Vancomycin was introduced in 1958 as an antibiotic active against Gram-positive cocci, particularly streptococci, staphylococci, and pneumococci. It is not active against Gram-negative bacteria, with the exception of Neisseria spp. Vancomycin is recommended for use when infections fail to respond to treatment with the more common antibiotics or when the infection is known to be caused by a resistant organism. It is particularly effective for the treatment of endocarditis caused by Gram-positive bacteria.
Vancomycin hydrochloride is a free-flowing, tan to brown powder that is relatively stable in the dry state. It is very soluble in water and insoluble in organic solvents. The salt is quite stable in acidic solutions. The free base is an amphoteric substance, whose structure was determined by a combination of chemical degradation and nuclear magnetic resonance (NMR) studies and x-ray crystallo-graphic analysis of a close analog.233 Slight stereochemical and conformational revisions in the originally proposed structure were made later.234,235 Vancomycin is a gly-copeptide containing two glycosidically linked sugars, glucose and vancosamine, and a complex cyclic peptide agly-con containing aromatic residues linked together in a unique resorcinol ether system.
Vancomycin inhibits cell wall synthesis by preventing the synthesis of cell wall mucopeptide polymer. It does so by binding with the d-alanine-d-alanine terminus of the uridine diphosphate-^-acetylmuramyl peptides required for mucopeptide polymerization.236 Details of the binding were elucidated by the elegant NMR studies of Williamson et al.237 The action of vancomycin leads to lysis of the bacterial cell. The antibiotic does not exhibit cross-resistance to ^-lactams, bacitracin, or cycloserine, from which it differs in mechanism. Resistance to vancomycin among Gram-positive cocci is rare. High-level resistance in clinical isolates of enterococci has been reported, however. This resistance is in response to the inducible production of a protein, encoded by vancomycin A, that is an altered ligase enzyme that causes the incorporation of a d-alanine-d-lactate depsipeptide instead of the usual d-alanine-d-ala-nine dipeptide in the peptidoglycan terminus.238 The resulting peptidoglycan can still undergo cross-linking but no longer binds vancomycin.
Vancomycin hydrochloride is always administered intravenously (never intramuscularly), either by slow injection or by continuous infusion, for the treatment of systemic infections. In short-term therapy, the toxic side reactions are usually slight, but continued use may lead to impaired auditory acuity, renal damage, phlebitis, and rashes. Because it is not absorbed or significantly degraded in the GI tract, vancomycin may be administered orally for the treatment of staphylococcal enterocolitis and for pseudomembranous colitis associated with clindamycin therapy. Some conversion to aglucovancomycin likely occurs in the low pH of the stomach. The latter retains about three fourths of the activity of vancomycin.
Teicoplanin (Teichomycin A2, Targocid) is a mixture of five closely related glycopeptide antibiotics produced by the actinomycete Actinoplanes teichomyceticus.239,240 The teicoplanin factors differ only in the acyl group in the northernmost of two glucosamines glycosidically linked to the cyclic peptide aglycone. Another sugar, d-mannose, is common to all of the teicoplanins. The structures of the teicoplanin factors were determined independently by a combination of chemical degradation241 and spectroscopic242,243 methods in three different groups in 1984.
The teicoplanin complex is similar to vancomycin structurally and microbiologically but has unique physical properties that contribute some potentially useful advantages.244 While retaining excellent water solubility, teicoplanin has significantly greater lipid solubility than vancomycin. Thus, te-icoplanin is distributed rapidly into tissues and penetrates phagocytes well. The complex has a long elimination halflife, ranging from 40 to 70 hours, resulting from a combination of slow tissue release and a high fraction of protein binding in the plasma (—90%). Unlike vancomycin, teicoplanin is not irritating to tissues and may be administered by intramuscular or intravenous injection. Because of its long half-life, teicoplanin may be administered on a once-a-day dosing schedule. Orally administered teicoplanin is not absorbed significantly and is recovered 40% unchanged in the feces.
Teicoplanin exhibits excellent antibacterial activity against Gram-positive organisms, including staphylococci, streptococci, enterococci, Clostridium and Corynebacterium spp., Propionibacterium acnes, and L. monocytogenes. It is not active against Gram-negative organisms, including Neisseria and Mycobacterium spp. Teicoplanin impairs bacterial cell wall synthesis by complexing with the terminal d-alanine-d-alanine dipeptide of the peptidoglycan, thus preventing cross-linking in a manner entirely analogous to the action of vancomycin.
In general, teicoplanin appears to be less toxic than van-comycin. Unlike vancomycin, it does not cause histamine release following intravenous infusion. Teicoplanin apparently also has less potential for causing nephrotoxicity than vancomycin.
The organism from which Johnson et al.245 produced bacitracin in 1945 is a strain of B. subtilis. The organism had been isolated from debrided tissue from a compound fracture in 7-year-old Margaret Tracy, hence the name "baci-tracin." Bacitracin is now produced from the licheniformis group (B. subtilis). Like tyrothricin, the first useful antibiotic obtained from bacterial cultures, bacitracin is a complex mixture of polypeptides. So far, at least 10 polypeptides have been isolated by countercurrent distribution techniques: A, A1, B, C, D, E, F1, F2, F3, and G. The commercial product known as bacitracin is a mixture of principally A, with smaller amounts of B, D, E, and F1-3.
The official product is a white to pale buff powder that is odorless or nearly so. In the dry state, bacitracin is stable, but it rapidly deteriorates in aqueous solutions at room temperature. Because it is hygroscopic, it must be stored in tight containers, preferably under refrigeration. The stability of aqueous solutions of bacitracin is affected by pH and temperature. Slightly acidic or neutral solutions are stable for as long as 1 year if kept at a temperature of 0 to 5°C. If the pH rises above 9, inactivation occurs very rapidly. For greatest stability, the
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