Mechanisms of Resistance

Mechanism of Resistance. Recendy, resistance to high levels of dalbaheptides has been described in both E.faecium and E.faecalis (111). 

This resistance, inducible by low concentrations of dalbaheptides, is plasmid mediated and is transferable. Concomitant with the induction of resistance is the appearance or increased expression of a protein having a molecular weight of either 39,500 or 39,000. The enzymatic activity of this material has been postulated (112). Although the mechanism of resistance induction by dalbaheptides is unknown, different dalhabaheptides have different induction capacity. Vancomycin (39) is the most powerful inducer teicoplanin is a very weak inducer. 

Research and clinical experience on dmg resistance suggests that tumor cells are particularly adept at genetic selections leading to alterations in the stmcture, function, or synthesis of proteins involved in the antitumor dmg action and detoxification. Multiple mechanisms of resistance have been shown to account for the resistance seen in the clinic (46). 

Mechanism of resistance to macrolides of their producers and eubacteria 98MI4. 

The major mechanism of resistance to chloramphenicol is mediated by the chloramphenicol acetyltransferases (CAT enzymes) which transfer one or two acetyl groups to one molecule of chloramphenicol. While the CAT enzymes share a common mechanism, different molecular classes can be discriminated. The corresponding genes are frequently located on integron-like structures and are widely distributed among Gramnegative and - positive bacteria. 

Wang J, Jin Y, Rapp KL, Schinazi RF, Chu CK (2007) D- and L-2, 3 -didehydro-2, 3 -dideoxy-3 -fluoro-carbocyclic nucleosides synthesis, anti-HIV activity and mechanism of resistance. J Med Chem 50 1828-1839... 

A general mechanism of resistance is reducing the affinity of the antiretroviral compound for its mutant target protein. Resistance mutations associated with reduced affinity are observed during treatment failure with a fusion inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTl), integrase inhibitor, and protease inhibitors as reviewed in Chaps. 3,4, 6, and 7 (Hazuda et al. 2007 Hsiou et al. 2001 King et al. 2002 Mink et al. 2005). 

McCaffery, A.R., GladweU, R.T., and El-Nayir, H. et al. (1991). Mechanisms of resistance to pyrethroids in laboratory and field strains of Heliothis virescens. Southwestern Entomologist Supplement 15, 143-158. 

Sjut, V. (Ed.) (1997). Molecular mechanisms of resistance to agrochemicals. In Chemistry of Plant Protection 13, Springer Berlin. 

Thijssen, H.H.W. (1995). Warfarin-based rodenticides mode of action and mechanism of resistance. Pesticide Science 43, 73-7S. 

Further studies on the mechanism of resistance of aminoglycoside antibiotics focused on resistance genes existing in antibiotic-producer strains (mainly by Drs. Y. Okami and Kunimoto Hotta), and gradually clarified the relationship between the antibiotic-producing and -regulating mechanism. During this search, indolizomycin (1984) was discovered by cell fusion of two kinds of strains. 

Biochemical mechanism of resistance to aminoglycosidic antibiotics, H. Umezawa, Adv. Carbohydr. Chem. Biochem., 30 (1974) 183-225. 

Biochemical mechanisms of resistance 3.5 Multidrug resistance pumps... 

Before eonsidering specific mechanisms of resistance for particular classes of antibiotic it is worth considering potential mechanisms of resistance in bacterial cells. These are summarized in Fig. 9.1 and specific examples are listed in Table 9.3. 

These mechanisms of resistance rely on reducing or preventing access of antibiotic to their target sites, but other mechanisms of resistance involving the target sites themselves can be considered. Alterations in the target site which reduce the binding of... 

Fig. 9.1 Schematic representation of possible mechanisms of resistance in Gram-negative and Gram-positive bacteria. 1, antibiotic-inactivating enzymes 2, antibiotic efflux proteins 3, alteration or duplication of intracellular targets 4, alteration of the cell membrane reducing antibiotic uptake 5, alterations in porins or lipopolysaccharide reducing antibiotic uptake or binding.

The following sections describe the biochemical mechanisms of resistance to different classes of antibiotics, with the antibiotics grouped according to their mechanism of action. 

Chromosomal mutations in E. coli result in overproduction of dihydrofolate reductase (DHFR). Higher concentrations of trimethoprim, which may not be therapeutically achievable, are therefore required to inhibit nucleotide metabolism. Other mutations lower the affinity of DHFR for trimethoprim. These two mechanisms of resistance may coexist in a single strain, effectively increasing the level of resistance to the antibiotic. 

Three mechanisms of resistance to the aminoglycoside-aminocyclitol (AGAC) group of antibiotics are recognized (Shaw et al. 1993). 

Plasmid- or transposon-encoded ribosomal protection factors are a second mechanism of resistance to the tetracyclines. These proteins are believed to alter the tetracycline binding site on the 308 ribosomal subunit, lowering the affinity for the drugs. 

These three classes of antibiotics are often grouped together because of their similar mode of action. They share a common mechanism of resistance, but there are some mechanisms specific to each group (Leclerq Courvalin 1991). 

A second mechanism of resistance involves alterations in PBPs which affect binding of /3-lactams. These changes have been found to occur by multiple substitutions through recombination rather than point mutations. Acquired penicillin resistance in Strep, pneumoniae is because of such gene mosaics which code for an altered yet functional PBP with reduced affinity for penicillin. Sections of the susceptible PBP gene have been replaced by other DNA sequences, presumably via transformation. 

These different types of microorganisms are considered below whenever possible, the mechanisms of resistance will be considered and the clinical or pharmaceutical relevance discussed. 

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

Ghannoum MA, LB Rice (1999) Antifungal agents mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev 12 501-517. 

Perea S, JL Lopez-Ribot, WR Kirkpatrick, RK McAtee, RA Santillan, M Martinez, D Calabrese, D Sanglard, TP Patterson (2001) Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antibicrob Agents Chemother 45 2676-2684. 

A considerable amount of the gold that accumulates in the kidneys and liver of mammalian species is bound to MTs. This buildup of gold in the kidneys is accompanied by elevated levels of renal copper to form copper-rich, gold-bearing MTs. In cell lines that overproduce MT, there is commonly a resistance to the cytotoxic effects of gold compounds. This resistance is also seen often in parent lines that have been repeatedly exposed to gold complexes. The mechanisms of resistance include but are not limited to enhanced biosynthesis of MT [102]. 

---