Fungal antibiotics

Dehydroalanine (Dha) and dehydro-a-aminobutyric acid, a putative dehydration product of threonine occur accumulated in a particular class of antibiotic fungal peptides recently named lantibiotics of which Nisin (Fig. 26) will be mentioned first. The structure of the 34-peptide as revealed by Erhard Gross and coworkers in the beginning of the seventies, contains three dehydro side chains, RCH=C(NH—)CO—, and five thioether amino acids, lanthionine, Ala-S-Ala and its homolog Abu-S-Ala. Total synthesis by the group of Tetsuo Shiba (Plate 43) [61]. 

Vinyl sulfoxide isomerization followed by Mislow-Evans rearrangement was also central to a S5mthetic route toward the hydroazulene moiety of the antibiotic fungal metabolite guanacastepene A fScheme 18.611. In this case, a diastereomeric mixture of vinyl sulfoxides 241 resulted upon oxidation of the starting vinyl sulfide 240. Subsequent treatment with DBU led to the sequential isomerization/[2,31-rearrangement process. Under these conditions, the intermediate sulfenate was converted to the allylic alcohol 242, produced as a 4 1 mixture of epimers. Here, the modest selectivity in formation of the allylic stereocenter was of no synthetic consequence, as the alcohol was subsequendy oxidized to the corresponding enone. Notably, the overall conversion from 240 to 242 represents a 1,3-vinyl-to-allyl heteroatom transposition. 

Table 15 gives a sampling of other pharmaceuticals derived from hydraziae. Cefazolin, a thiadiazole tetrazole derivative, is one of the most widely used antibacterial dmgs in U.S. hospitals (see Antibiotics, P-LACTAMs). Procarbazine, an antineoplastic, is a monomethyUiydrazine derivative (220). Fluconazole has shown some promise in the treatment of AIDS-related fungal infections. Carbidopa is employed in the treatment of Parkinson s disease. FurazoHdone is a veterinarian antibacterial. 

Pneumogstis carini pneumonia (PCP), the most common of the opportunistic infections, occurs in more than 80% of AIDS patients (13). Toxoplasmosis, a proto2oan infection of the central nervous system, is activated in AIDS patients when the 004 count drops and severe impairment of ceU-mediated immunity occurs. Typically, patients have a mass lesion(s) in the brain. These mass lesions usually respond well to therapy and can disappear completely. Fungal infections, such as CTyptococcalmeningitis, are extremely common in AIDS patients, and Histop/asma capsulatum appears when ceU-mediated immunity has been destroyed by the HIV vims, leading to widespread infection of the lungs, Hver, spleen, lymph nodes, and bone marrow. AIDS patients are particularly susceptible to bacteremia caused by nontyphoidal strains of Salmonella. Bacteremia may be cleared by using antibiotic therapy. 

A number of fungal immunosuppressives have been isolated from fermentation broths and demonstrated to have immunotherapeutic efficacy. Other than cyclosporin (35), two fungal metaboHtes, sirolimus (36), previously known as rapamycin (80), and FK-506 (37) (81) are in various stages of development (see Antibiotics, macrolides). 

Most peptide antibiotics have been isolated from Jictinomycetes and especially from Streptomjces. Many P-lactams, however, and a few other useful peptide antibiotics have come from fungi. These streptomycete and fungal peptide antibiotics include many stmctural types having varied therapeutic indications and/or scientific appHcations. 

A few natural products with oxirane rings fused to five-membered rings are known. These include the antibiotic methylenomycin-A (82) (79H(13)353, 79JOC4210,80JA3904, 81CC714) and the truly remarkable fungal metabolite trichoviridine (83), which appears to be the first example of an isocyanide epoxide (76CPB832). 

A possible example of this thesis is the crystalline insect toxin found in Bacillus thuringiensis spores and discussed here by Dr. Anderson. Although neither the bacillus nor its spores exhibit useful antibiotic activity against other microorganisms, the very specific toxicity to insects has become of major commercial interest. The enormous number and variety of fungal species available for further examination must lead inevitably to one or more which produces pesticidal metabolites. 

Amphotericin B, is a polyene antibiotic, used in the therapy of systemic fungal infections. Its mode of action exploits differences in membrane composition between the pathogen and the human host. Ergosterol, the predominant sterol of fungi, plants, and some protozoan parasites, interacts with Amphotericin B, resulting in an increased ion permeability of the membrane. Humans contain cholesterol, which has a low affinity for amphotericin B. 

Before therapy is begun, culture and sensitivity tests (see Chap. 7) are performed to determine which antibiotic will best control the infection. These drug are of no value in the treatment of infections caused by a virus or fungus. There may be times when a secondary bacterial infection has occurred or potentially will occur when the patient has a fungal or viral infection. The primary health care provider may then order one of die... 

The glucocorticoids are contraindicated in patients widi serious infections, such as tuberculosis and fungal and antibiotic-resistant infections. 

The antibiotic and sulfonamide ophthalmics are contraindicated in patients with a hypersensitivity to the drug or any component of the drug. These dru are also contraindicated in patients with epithelial herpes simplex keratitis, varicella, mycobacterial infection of the eye, and fungal diseases of the eye There are no significant precautions or interactions when the dru are administered as directed by the primary health care provider. 

In contrast to the wide range of antibacterial antibiotics, there are very few antifungal antibiotics that can be used systemically. Lack of toxicity is, as always, of paramount importance, but the differences in structure of, and some biosynthetic processes in, fungal cells (Chapter 2) mean that antibacterial antibiotics are usually inactive against fungi. 

Sterile pharmaceutical preparations must be tested for the presence of fungal and bacterial contamination before use (see Chapters 18 and 23). If the preparation contains an antibiotic, it must be removed or inactivated. Membrane filtration is the usual recommended method. However, this technique has certain disadvantages. Accidental contamination is a problem, as is the retention of the antibiotic on the filter and its subsequent liberation into the nutrient medium. 

Fungal endocarditis is quite uncommon but has significant mortality, typically affecting patients who have had cardiovascular surgery, received a prolonged course of broad-spectrum antibiotics, have long-term catheter placement, are immunocompromised, or are IVDUs.8,35 Survival rates have remained... 

Monitor the patient for the development of potential complications of treatment such as delayed hypersensitivity reactions, antibiotic-induced diarrhea, pseudomembraneous colitis, or fungal superinfections (manifested as oral thrush). 

Septic patients not responding to conventional antibiotics should be evaluated for fungal infections. Candida albicans is the most common fungal species however, the prevalence of non-albicans species is increasing. Amphotericin B is utilized in septic patients with fungal or suspected fungal infections... 

Use of antibiotics Altered flora of mucosa allowing fungal overgrowth... 

The current induction therapy for acute myelogenous leukemia (AML) usually consists of a combination of cytara-bine and daunorubicin, with the frequent addition of a steroid and/or an antimetabolite such as 6-thioguanine. The risk of infection is so high during this period that patients receive antibiotic and fungal prophylaxis. 

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