Rifampicin resistance

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

Nucleotidylation - the addition of adenylate-residues by Lnu enzymes - can also be the cause of resistance to lincosamide antibiotics in staphylococci and enterococci. A plasmid encoded ADP-ribosylating transferase (Arr-2) that leads to rifampicin resistance has been detected in various Enterobacteriaceae as well as in Pseudomonas aeruginosa. 

Soro O, Pesce A, Raggi M, Debbia EA, Schito GC Selection of rifampicin-resistant Mycobacterium tuberculosis does not occur in the presence of low concentrations of rifaximin. Clin Microbiol Infect 1997 3 147-151. 

Mycobacteria are also killed in vitro, as expected from an antibiotic sharing the properties of the rifamycin family [24], In a study by Soro et al. [25], the MIC of rifaximin was determined for five Mycobacterium tuberculosis isolates from patients with tuberculosis. MIC concentrations were studied at 6, 20, 90 and 270 pg/ml, respectively. No resistant organisms were found. Growing M. tuberculosis in the presence of varying doses of rifaximin did not induce the occurrence of rifampicin-resistant strains [25]. In addition to this, experimental tubercular infection in the guinea pig was found not to be affected by an oral treatment course with rifaximin, therefore confirming the lack of absorption of the molecule after oral administration [26],... 

It is bactericidal and highly effective in leprosy. A single monthly dose of 600 mg may be used in combination with other antileprosy drugs to avoid any probable risk of rifampicin resistant M. leprae. 

Detection of Rifampicin-Resistant Strains of Tuberculosis Rifampicin is an important antibiotic used to treat tuberculosis, as well as other mycobacterial diseases. 

Some strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, are resistant to rifampicin. These strains become resistant through mutations that alter the rpoB gene, which encodes the /3 subunit of the RNA polymerase. Rifampicin cannot bind to the mutant RNA polymerase and so is unable to block the initiation of transcription. DNA sequences from a large number of rifampicin-resistant M. tuberculosis strains have been found to have mutations in a specific 69 bp region of rpoB. One well-characterized strain with rifampicin resistance has a single base pair alteration in rpoB that results in a single amino acid substitution in the J3 subunit a His residue is replaced by an Asp residue. 

Bjerrum et al. (2005) reported the results of an experiment involving broilers infected with a rifampicin-resistant Salmonella typhimurium strain at 15 days of age. Lower numbers of the organism were found in the gizzard and ileum of birds receiving whole wheat compared with pellet-fed birds. 

Drobniewski FA, Watterson SA, Wilson SM, Harris GS. A clinical, microbiological and economic analysis of a national service for the rapid molecular diagnosis of tuberculosis and rifampicin resistance in Mycobacterium tuberculosis. J Med Microbiol 2000 49 271-278. 

Plate the 10 6 dilution of each of the overnight cultures, including the control, on agar plates to monitor the presence of viable cells. To look for rifampicin-resistant (Rif) mutants, plate undiluted and a 10 1 dilution ofthe control and a 10 2 dilution for each mutagenized culture on agar plates with rifampicin (100 p,g/mL). 

Bouche, J.-P., Zechel, K., Komberg, A. DNA G gene product, a rifampicin resistant RNA polymerase, initiates the conversion of a single-stranded coliphage DNA to its duplex replicative form. J. Biol. Chem. 250, 5995 (1975)... 

Sippel, A., Hartmann, G. Rifampicin resistance of RNA polymerase in the binary complex with DNA. Europ. J. Biochem. 16, 152 (1970)... 

Zimmermann, W., Wehrli, W. Rifampicin resistance in E. coli comparison of microbiological and enzymatic properties. Experientia 33, 132 (1976)... 

Wozny, M.E., Camevale, H.N., Jones, E.E. Alteration of regulation of arginine biosynthesis in E. coli W by mutation to rifampicin resistance. Biochim. Biophys. Acta 383,106 (1975)... 

Wintersberger, E. Isolation of a distinct rifampicin-resistant RNA polymerase from mitochondria of yeast, neurospora and liver. Biochem. Biophys. Res. Comm. 48, 1287 (1972)... 

Rifampicin must bind to the (3 subunit of RNA polymerase to inhibit the enzyme. A mutation in the gene encoding this subunit that would interfere with the binding of the antibiotic but not with polymerization would produce a rifampicin-resistant cell. 

Yu, J., Wu, J., Francis, K. P., Purchio, T. F., and Kadurugamuwa, J. L. (2005) Monitoring in vivo fitness of rifampicin-resistant Staphylococcus aureus mutants in a mouse biofilm infection model. J. Antimicrob. Chemother. 55, 528-534. 

Rifamycins act on the j8-subunit of the protein in bacterial DNA-dependent RNA polymerase. Combination is tight, though not covalent, and occurs in a 1 1 molecular ratio (this union does not take place in rifampicin-resistant organisms). As a result, no more RNA is synthesized, but neither DNA nor protein syntheses are affected. There is no action whatsoever on the RNA-synthesizing mechanism of mammals, which lacks a )8-subunit, and hence the selectivity experienced by the patient is of the very highest degree (Tocchini-Valenti, Marino and Colvill, 1968). 

It was found that the macrocyclic ring of rifamycin was responsible for the complex formation of the antibiotic with E. coli RNA polymerase and for the inhibitory effect of the antibiotic on the enzyme. Changes in other parts of the molecule have little effect on the direct action on E. coli RNA polymerase but may affect its permeability characteristics . Some derivatives of rifamycin, prepared by substitution with cyclic secondary amines, displayed activity against rifampicin resistant mutants of Staphylococcus aureus . ... 

Drug-drug interactious Lopinavir - - ritonavir The steady-state pharmacokinetics of rifabutin and its active metabolite 25-desacetyl-rifabutin have been examined before and after the addition of lopinavir - -ritonavir in 10 patients with HIV infection and active tuberculosis [79 ]. Samples were collected at 2-4 weeks after starting rifabutin 300 mg thrice weekly without lopinavir -I- ritonavir, 2 weeks after the addition of lopinavir -I- ritonavir 400/100 mg bd to rifabutin 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the target range) 2 weeks after an increase in rifabutin dosage to 300 mg thrice weekly with lopinavir + ritonavir. Lopinavir - -ritonavir reduced the Cmax of total rifabutin and most unbound rifabutin C ax values were below the tuberculosis MIC. For most patients, the AUC was low or lower than associated with treatment failure or relapse and with acquired rifampicin resistance. The authors concluded that the recommended doses of rifabutin for use with lopinavir -I- ritonavir may be inadequate in many patients and recommended monitoring of plasma concentrations. 

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