Polyenes resistance

Sterol Changes and Resistance. DMI-resistant mutants of U. maydls lacking 14DM have been isolated (32). These mutants, which were initially selected for polyene resistance, have no detectable demethyl sterols and grow more slowly than wild-type... 

It is often stated that resistance to polyene antibiotics does not occur [103, 299—301). It is perhaps more true to say that although yeasts and other fungi are capable of giving rise to polyene-resistant strains, polyene resistance has not become a clinical problem, even after twenty years of therapeutic use. This is fortunate, for an increase in resistance of twenty-fold would be sufficient to render many strains of pathogenic and opportunistic fungi resistant to antibiotic concentrations that can be achieved in clinical lesions by conventional polyene therapy. 

In vitro polyene resistance has been demonstrated in yeasts [301-311], dermatophytes [312,313], Aspergillus sp. [314] and Neurospora sp. [315]. Resistance to polyenes does not confer resistance to non-polyene antifungal... 

Relatively few reports exist of in vivo acquisition of polyene resistance and those cases reported only possessed low levels of resistance (three to four times the minimum inhibitory concentration) [336,337]. Examination of large numbers of clinical isolates of C. albicans has failed to demonstrate resistance to... 

A series of papers [305—310,323] examined the genetics of polyene resistance in S. cerevisiae and suggested that nystatin resistance was controlled by three recessive genes and two dominant modifiers. Thf genes that gave rise to the s-l, nys-2 and nys-3 mutants differed markedly in their ability to give crossresistance to filipin and amphotericin B, nys-l confered resistance to amphotericin B and nystatin but not to filipin, while nys-2 and nys-3 confered resistance to nystatin and filipin but made the yeasts hypersensitive to amphotericin... 

C. albicans [311]. Also described were cytoplasmic polyene-resistant mutants which gave complete cross-resistance to all polyenes tested [305]. 

Polyene Resistance - Two of 51 in vitro induced nystatin resistant strains of Cryptococcus neoformans showed cross resistance to amphotericin B.l >121 Studies using three in vitro induced nystatin resistant mutants of Saccharomyces cerevisiae indicated that cross resistance correlated with polyene size.122 variants of Candida albicans resistant to... 

In neutral polyenes a clear distinction can be made between essential single bonds (which can be twisted fairly easily) and double bonds (which offer much more resistance to rotation). It has become customary to distinguish stable isomers (classified E/Z with regard to the configuration around the double bonds) and easily interconvertible conform-ers (classified as s-cis, s-trnns or gauche with regard to the substituents on the essential single bonds) in polyenes. 

Because of the enhanced rigidity of the higher-membered heteroannulenes, e.g. (36), imparted chiefly by the presence of properly positioned trans double bonds, these frames are generally less thermally labile than their heteronin counterparts although here too aromatic derivatives are substantially more heat resistant than their polyenic relatives. It was noted, for example (75PAC(44)69l), that while parent aza[13]annulene (37a) is thermally stable at 56 °C, its polyenic acetamide (36a) readily rearranges ( i/2< 1 h) under these conditions to what is believed to be a tricyclic isomer (96). 

While initial aging did cause some loss in volume resistivity, it was no more severe in unstabilized than in stabilized compositions. The most startling effect was the marked increase in volume resistivity under severe aging conditions. This may be due to volatilization loss of DOP or cross-linking of polyvinyl chloride, both of which could reduce migration of ionic impurities, or it may involve adsorption of ionic impurities by the dark-colored, conjugated, polyene structure which forms by loss of hydrogen chloride. In any case it deserves further study. 

As films are used e.g. the polymerization product of ethylbenzene and divinylbenzene (33) the copolymer of styrene and butadiene (755) the copolymer of styrene and butadiene mixed with polyethylene (157) a vulcanized or cyclized copolymer of an aromatic vinylcompound and an aliphatic conjugated polyene (2). As a crack resisting matrix is mentioned the copolymer of styrene, divinylbenzene and butadiene with e.g. dioctylphthalate as a plasticizer (176). Other examples are the copolymers of unsaturated aromatic compounds and unsaturated aliphatic compounds (77) and the reaction products of polyolefines and partially polymerized styrene (174). Primary groups can be introduced also with the help of Friedel-Crafts catalyst. Ts. Kuwata and co-workers treated a film of a copolymer of styrene and butadiene with an aluminium-ether complex and ethylenedichloride (79). Afterwards they allowed the film to react with trimethylamine. Another technique is the grafting of e.g. a polyethylene film with styrene (28). 

Andrus MB, Turner TM, Sauna ZE, Ambudkar SV, The synthesis and evaluation of a solution phase indexed combinatorial library of non-natural polyenes for reversal of P-glycoprotein mediated multidrug resistance, J. Org. Chem., 65 4973-4983, 2000. 

Nystatin [nye STAT in] is a polyene antibiotic its structure, chemistry, mode of action, and resistance resemble those of amphotericin B. Its use is restricted to topical treatment of Candida infections because of its systemic toxicity. The drug is negligibly absorbed from the gastrointestinal tract, and it is never used par-enterally. It is administered as an oral agent ( swish and swallow ) for the treatment of oral candidiasis. Excretion in the feces is nearly quantitative. Adverse effects are rare because of its lack of absorption, but occasionally nausea and vomiting occur. 

One compound that has been associated with distal tubular injury is amphotericin B, a polyene antifungal agent used in the treatment of systemic mycoses caused by opportunistic fungi. Clinical utility of amphotericin B is limited by its nephrotoxicity, characterized functionally by polyuria resistant to antidiuretic hormone administration, hyposthenuria, hypokalemia, and mild renal tubular acidosis. 

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