Rifampicin structure

Figure 3.6 Comparison of the chemical structures of rifamycin (Rifampicin ) and rifamycin CGP 4832 the latter is transported by FhuA. Note the entirely different chemical structures (Figure 3.2) and conformations (Figure 3.5) of the ferrichrome and albomycin FhuA transport substrates.

Fig. 2. Chemical structures of rifampicin and rifaximin as well as of their parent compound, rifamycin SV. The empirical formula of rifaximin is C43H51N3O11 and its molecular weight 785.9 daltons.

Antimicrobial resistance to rifamycins develops rapidly both in vitro and in vivo [65,85,86], As a consequence, all the three members of the family (i.e. rifampicin, rifabutin and rifapentine) are used clinically as components of combination therapies [65,87], Being structurally related, rifaximin could share this potential. And indeed resistance rates, recorded in fecal strains of Enterobacteriaceae, Enterococcus, Bacteroides, Clostridium and anaerobic cocci, ranged between 30 and 90% after short-term (5 days) antibiotic (800 mg daily) treatment [82], A similar pattern was observed in 10 patients with hepatic encephalopathy after treatment with rifaximin 1,200 mg/day for 5 days [80]. 

Fig. 4.7 Structures of (A) rifamycin, (B) rifampicin and (C) rifabutin, together with their pharmacokinetic properties. Voiume of distribution V i) and plasma clearance (Cip) are for free unbound drug.

Fig. 8.29 Structures of known clinical CYP3A4 inducers nevirapine (A), troglitazone (B), phenobarbitone (C), efavirenz (D), probenicid (E), phenytoin (F), moricizine (G), felbamate (H), rifampicin (I) and carba-mazepine (J).

Many experiments could be carried out either as paired or unpaired studies. For example the rifampicin/theophylline experiment (Table 6.1) was performed on an unpaired basis -15 people received one treatment and a separate group of 15 received the other. This is referred to as a parallel groups trial. We could have used a paired structure, with 15 subjects receiving one treatment on one occasion and the other treatment at some other time (a cross over trial). The paired alternative would almost certainly have been a lot more powerful. However, it does not follow automatically that we should always be looking for a paired experimental design. The following points need to be born in mind ... 

Figure 13.2. Rat and human UGT2A and 2B proteins have a structure similar to that of UGT1A, consisting of divergent and common (or conserved) regions. Some of UGT genes are inducible by phenobarbital or rifampicin through activation of SXR or CAR, heterodimer formation with RXR and bind to regulatory elements in the UGT genes.

Several hundred semisynthetic derivatives have been prepared in an effort to obtain substances with better biological activities (for references see Ref.s)). Particularly positions 3 and 4 of the naphthoquinone ring system (numbering system as proposed by Prelog7 8) have been extensively substituted, since it has been shown that structural changes in these two positions do not critically affect the action of the substance on the target enzyme, the bacterial RNA polymerase (cf. Chapter 3.). They can, however, influence other parameters such as its ability to penetrate into cells, its pharmacokinetic properties and resorption, which are all important for clinical use as an antibiotic. Rifampicin (U.S. rifampin), which is a widely used orally active tuberculostatic agent, is a 3-(4-methyl piperazinyl)-iminomethyl derivative of rifamycin SV, synthesized via the 3-formyl derivative (Fig. 5)10 ... 

The structure of the ansamycins determines not only their activity on RNA polymerase, but also other important characteristics such as their ability to penetrate into bacteria and their pharmacokinetics and absorption in the host. To cite just a few examples rifamycin B, containing a free carboxylic acid group, has no antibacterial activity, although it inhibits RNA polymerase as strongly as rifampicin. Damavaricin C behaves similarly to rifamycin B, whereas its 6-methyl ether inhibits RNA polymerase to a lesser extent, but has good antibacterial activity23. Rifampicin owes its widespread clinical use to the fact that, in contrast to most other rifamycin derivatives, it is well absorbed when given orally. 

Chrencik JE, et al. Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. 

This antibiotic specifically inhibits the initiation ofRNA synthesis. Rifampicin does not block the binding of RNA polymerase to the DNA template rather, it interferes with the formation of the first few phosphodiester bonds in the RNA chain. The structure of a complex between a prokaryotic RNA polymerase and rifampicin reveals that the antibiotic blocks the channel into which the RNA-DNA hybrid generated by the enzyme must pass (Figure 28.14). The binding site is 12 A from the active site itself Rifampicin does not hinder chain elongation once initiated, because the RNA-DNA hybrid present in the enzyme prevents the antibiotic from binding. 

E.A. Campbell, N. Korzheva, A. Mustaev, K. Murakami, S. Nair, A. Goldfarb, and S.A. Darst. 2001. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase Cell 104 901-912. (PubMed)... 

Amphoteridn is a complex amphoteric polyene antibiotic that binds to cell membranes and forms a pore through which ions can pass, with consequences that include loss of potassium ions from within the cell. Since the antibiotic binds more readily to fungal cell membranes than mammalian, its action is relatively selective. It can potentiate the action of certain other antifungals. and it may be used with flucytosine. Also, it confers antifungal activity on rifampicin (normally antibacterial). As it has an appreciable renal toxicity, it needs to be used with caution in some patients. Nystatin is a polyene antibiotic similar in structure to amphotericin, often used for local treatment. 

Chrencik JE, Orans JO, Moore LB, Xue Y, Peng L, Collins JL, et al. Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol Endocrinol 2005 19 1125-34. 

The answer is e. (Murray, pp 452-467. Scriver, pp 3-45. Sack, pp 1-40. Wilson, pp 101-120.) Puromycin is virtually identical in structure to the 3 -terminal end of tyrosinyl-tRNA. In both eukaryotic and prokaryotic cells, it is accepted as a tyrosinyl-tRNA analogue. As such, it is incorporated into the carboxy-terminal position ol a peptide at the aminoacyl (A) site on ribosomes, causing premature release of the nascent polypeptide. Thus, puromycin inhibits protein synthesis in both human and bacterial cells. Streptomycin, like tetracycline and chloramphenicol, inhibits ribosomal activity. Mitomycin covalently cross-links DNA, which prevents cell replication. Rifampicin is an inhibitor of bacterial DNA-dependent RNA polymerase. 

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