Rifampicin derivatives

Fig. 4.8 Typical generation rate curves of coli at 37 °C in the absence (+) and presence of 2 LI M of various rifampicin derivatives possessing different lipophilic properties (log k,). The variation in lag phase (onset of inhibition) is clearly shown. (Reprinted from Fig. 1 of ref. 105.)...

Rifampicin has also shown antiviral activity but at levels 500—1000 times greater than required for antibacterial activity (130,140—142). Rifampicin shows promise in the treatment of leprosy (130,143). A large number of rifampicinlike derivatives are potent inhibitors of reverse transcriptase (123,144-148). 

A number of oxime derivatives of rifaldehyde have been prepared. Many of these derivatives exhibit good activity against rifampicin-resistant organisms (151,152). 

Rifampicin, the only commercially available ansamacroHde, is manufactured by MerreU Dow under the tradename Rifadin, and by CIBA under the trade name Rimactane. Rifampicin is also suppHed in combination with isoniazid or pyrazinamide [98-96-4]. The rifampicin—isoniazid combination is known as Rifamate (MerreU Dow), Rifinah (MerreU Dow), and Rimactazid (CIBA) the rifampicin—pyrazinamide as Rifater (MerreU Dow). Several other rifamycin derivatives including rifabutin and rifapentine are undergoing clinical studies. 

Rifampicin is the semisynthetic derivative used widely in the UK. Resistance to rifampicin is primarily due to chromosomal mutations resulting in an altered RNA polymerase which is less well inhibited by the drug. The mutations tend to be clustered within short conserved regions of the J3 subunit gene of RNA polymerase. Similar mutations have been found in all bacterial species studied thus far. 

The first study was performed by Venturini [97, 98] in both rats and dogs by using a microbiological assay (i.e. agar diffusion test and S. aureus 209 P FDA as test organism). Conversely from rifampicin, whose serum levels were already detectable 30 min after the administration and still measurable after 48 h, only trace amounts (i.e. 0.2 pg/ml) of rifaximin were detected in serum of fed rats 4 h later (fig. 6). The amount of detectable antibiotic was reduced by 50% in fasted animals. Similar results have been obtained in dogs after oral administration of 25 mg/ kg of both rifamycin derivatives [97, 98], No detectable amount of rifaximin was found in serum at any time. 

The broad antibacterial activity of rifaximin as well as its topical action make this antibiotic suitable for intrapocket administration in periodontal disease. As a matter of fact, local application of rifaximin compares well with tetracyclines and metronidazole in other extra-GI diseases, i.e. skin infections and BY, respectively (see above). On the other hand, rifampicin (rifampin), another rifamy-cin derivative, has been successfully used in the treatment... 

Rifamycin SV (133, Fig. 23) is a naturally occurring macrocycle isolated from Nocardia mediterranei by Senti, Greco and Ballotta in 1959. It shows a high in vitro antibiotic activity through inhibition of DNA-dependent RNA polymerase, but bioavailability is low due to its poor water solubility. The semisynthetic derivative rifampicin (135) displays markedly higher water solubility and in vivo activity. We chose 3-formylrifamycin (134) as model macrocycle for the possibility of binding it to solid phase by hydrazone bond formation in a manner similar to rifampicin (Fig. 24). 

Rifampicin is a semisynthetic derivative of rifamicin B, a macrolactam antibiotic and one of more than five antibiotics from a mixture of rifamicins A, B, C, D, and E, which is called a rifamicin complex, which is produced by actinomycetes Streptomyces mediteranei (Nocardia mediteranei). It was introduced into medical practice in 1968. Synthesis of rifampicin begins with an aqueous solution of rifamicin, which under the reaction conditions is oxidized to a new derivative of rifamicin S (32.7.4), with the intermediate formation of... 

Rifampicin Rifampicin is 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[Af-(4-methyl-l-piperaz inyl)-formamidoyl]-2,7-(epoxypentadeca-l,11-13-trienimino)-naphtho-[2,l-b] furane-l,ll(2H)dion-21 acetate (32.7.8). It is a semisynthetic derivative of rifamicin B, which is synthesized by the actinomycete Streptomyces medit-eranei (Nocardia mediteranei), and was introduced into medical practice in 1968. Rifampicin is described in Chapter 32. 

Among the antimycobacterials often a differentiation is made between first-choice and second-choice agents. The first-choice agents include iso-niazid, rifampicin, ethambutol, pyrazinamide and streptomycin or as alternatives the other aminoglycosides amikacine or kanamycine. The second-choice agents include the quinolones ciprofloxacin and ofloxacin and also the rifamycin derivative rifabutin. 

Rifampicin, a semisynthetic derivative of the antimicrobial agent rifamycin B obtained from Strep-tomyces mediterranei, is bactericidal for intra- and extracellular bacteria. Bacterial RNA synthesis is inhibited by binding to the beta-subunit of DNA-dependent RNA polymerase. Human polymerases are not affected. It has activity against gram-positive and gram-negative cocci, chlamydia as well as mycobacteria. It is used in combination with dapsone for leprosy. 

The rifamycins, a class of antibacterials isolated from Streptomyces mediterranei, contain a macrocyclic ring bridging across two nonadjacent positions on an aromatic system. Rifampicin (9.96), a semisynthetic derivative of rifamycin, is a drug of choice in the treatment of tuberculosis as well as leprosy, either alone or in combination with other drugs. Rifampicin is much safer than other antituberculotics since it inhibits DNA-directed RNA polymerase in bacteria but not in mammals. Another rifamycin, rifabutin (9.97), is a spiroimidazopiperidyl derivative of the rifamycin. 

Rifampicin is a synthetic derivative of a naturally occurring antibiotic, rifamycin, that inhibits bacterial DNA-dependent RNA polymerase but not T7 RNA polymerase or eukaryotic RNA polymerases. It binds tightly to the ft subunit. Although it does not prevent promoter binding or formation of the first phosphodiester bond, it effectively prevents synthesis of longer RNA chains. It does not inhibit elongation when added after initiation has occurred. Another antibiotic, streptolydigin, also binds to the ft subunit it inhibits all bond formation. 

A high-throughput assay for bacterial RNA polymerase has been successfully developed and validated using a 96-well, automated format [70], The reaction mixture contained a DNA template, nucleotide substrates (NTPs), supplemented with a-33P-labeled CTP in Tris-acetate buffer (pH 6.8). The polymerase reaction was carried out at 34°C for 40 min (providing linear kinetics). The effect of dimethylsulfoxide (DMSO), the usual solvent for test compounds used in a screen, was taken into consideration. The radiolabeled RNA transcripts were allowed to bind diethyl aminoethyl (DEAE) beads, which were then separated via filtration, and radioactivity associated with the wells was quantitated to measure the RNA polymerase activity. The standard deviation of the measured activity was typically < 15% of the average. Use of this assay to screen for RNA polymerase inhibitors from chemical libraries and natural products led to the identification of DNA intercalators (known to inhibit RNA polymerase activity), rifampicin (a known inhibitors of RNA polymerase), and several derivatives of rifampicin from Actinomycetes extracts. Therefore this assay can be reliably utilized to detect novel inhibitors of bacterial RNA polymerase. 

The implication for the therapeutic application of these rifampicins is quite obvious. Highly lipophilic derivatives may fail in therapy despite low in vitro MIC values (high intrinsic activity) because the time needed for the diffusion into the bacterial cell might be too long compared with their biological half-life (concentration-time profile in the serum). 

The antibiotic rifamycin and a semisynthetic derivative, rifampicin, specifically inhibit the initiation of RNA synthesis by interfering with the formation of the first phosphodiester bond of the RNA chain. The elongation of chains already being synthesized is unaffected. 

The whole logic of the paired /-test that we just performed was founded on the fact that we could calculate a change for each individual participant in the experiment and then use those changes to calculate the rest of the test. With the theophylline/ rifampicin experiment (Table 6.1), the data also consisted of two columns of data, but in that case there was no pairing. The first figure in the first column and that in the second column were derived from different individuals and it would have made no sense to start calculating the difference between these two figures and then move down to the second number in each column and so on. 

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 ... 

Certain ansamycin derivatives, such as rifampicin, inhibit the growth of these organisms at high drug concentration. The underlying mechanism of action is poorly unterstood at present, but it does not seem to be related to RNA or DNA synthesis. 

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. 

Most studies about the effects of ansamycins on DNA viruses have been made with vaccinia virus51l It has been found that some derivatives, such as rifampicin, inhibit the growth of this virus. There is no doubt, however, that this inhibition is not due to a block in RNA synthesis, as was found in bacteria, but apparently the assembly... 

Many antibiotics are highly specific inhibitors of biological processes. Rifampicin and actinomycin are two antibiotics that inhibit transcription, although in quite different ways. Rifampicin is a semisynthetic derivative of rifamycins, which are derived from a strain of Streptomyces. 

Rifabutin (rINN), a spiropiperidyl derivative of rifamy-cin, is more effective in vitro against M. tuberculosis than rifampicin. It has a longer half-life, better tissue penetration, and causes less enzyme induction than rifampicin. Rifabutin is well absorbed from the gastrointestinal tract and reaches a peak serum concentration of about 0.5 pg/ml 4 hours after a single dose of 300 mg. 

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