Rifampicin: A New Orally Active Rifamycin

Maggi, N; Pasqualucci, C.R.; Ballotta, R; Sensi, P

doi:10.1159/000220462

Cited by 247 publications

(117 citation statements)

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“…In marked contrast to penicillin, 2.2 times as much rifampin was found in the cell pellet as could be explained by rifampin in the extracellular fluid. Rifampin, which is a "zwitterion" (25), was also the only antibiotic (of 18 tested) that was able to penetrate leukocytes and kill ingested organisms. These same 18 antimicrobial compounds were studied to determine ability to diffuse through cottonseed oil and only rifampin could do this.…”

Section: Tmentioning

confidence: 99%

Interaction of Intraleukocytic Bacteria and Antibiotics

Mandell¹

1973

J. Clin. Invest.

198

110

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A B S T R A C T Bacteria that survive inside polymorphonuclear neutrophils (PMN) following phagocytosis are protected from the bactericidal action of most antibiotics. Two possible explanations are altered metabolism by intraleukocytic bacteria or failure of antibiotics to enter the phagosome. The oxygen consumption of intraleukocytic and extraleukocytic bacteria was measured as an index of bacterial metabolism. PMN respiration and bactericidal activity were suppressed with large doses of hydrocortisone and extraleukocytic bacterial oxygen consumption was abolished by the addition of lysostaphin. Intraleukocytic bacterial continued to consume oxygen suggesting that surviving ingested microorganisms are metabolically active. Neither penicillin (which cannot kill intraleukocytic bacteria) nor rifampin (which can kill intraleukocytic bacteria) was bactericidal for staphylococci at 5°C. Thus, rifampin is not uniquely able to kill "resting" bacteria. The total water space in the pellets was quantitated using tritium water and the extracellular water space was measured using Na2'5SO4. All penicillin associated with the cell pellet could be accounted for in extracellular water. Thus penicillin was completely excluded from the leukocytes. Rifampin was concentrated in the cell pellet 2.2 times when compared with the supernatant concentration.These studies suggest that a likely explanation for the survival of phagocytized bacteria in the presence of high concentrations of most antibiotics is the inability of the Dr. Mandell is the holder of a Research Career Development Award GM-49520 from the National Institute of General Medical Sciences.

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Section: Tmentioning

confidence: 99%

Interaction of Intraleukocytic Bacteria and Antibiotics

Mandell¹

1973

J. Clin. Invest.

198

110

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“…Synthetically modified derivatives, such as rifampicin, rifabutin and rifapentine, remain the principal chemotherapeutic agents used for combating tuberculosis, leprosy and AIDS-related mycobacterial infections (Maggi et al, 1966;Ramos-e-Silva & Rebello, 2001;Sepkowitz et al, 1995). The potent antibacterial activity of this class of antibiotics is due to their specific inhibition of bacterial DNA-dependent RNA polymerases (Campbell et al, 2001;Wehrli & Staehelin, 1969).…”

Section: Introductionmentioning

confidence: 99%

Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699

et al. 2005

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Rifamycin B biosynthesis by Amycolatopsis mediterranei S699 involves a number of unusual modification reactions in the formation of the unique polyketide backbone and decoration of the molecule. A number of genes believed to be involved in the tailoring of rifamycin B were investigated and the results confirmed that the formation of the naphthalene ring moiety of rifamycin takes place during the polyketide chain extension and is catalysed by Rif-Orf19, a 3-(3-hydroxyphenyl)propionate hydroxylase-like protein. The cytochrome P450-dependent monooxygenase encoded by rif-orf5 is required for the conversion of the D12, 29 olefinic bond in the polyketide backbone of rifamycin W into the ketal moiety of rifamycin B. Furthermore, Rif-Orf3 may be involved in the regulation of rifamycin B production, as its knock-out mutant produced about 40 % more rifamycin B than the wild-type. The work also revealed that many of the genes located in the cluster are not involved in rifamycin biosynthesis, but might be evolutionary remnants carried over from an ancestral lineage. INTRODUCTIONRifamycin continues to play a significant role in clinical medicine. Synthetically modified derivatives, such as rifampicin, rifabutin and rifapentine, remain the principal chemotherapeutic agents used for combating tuberculosis, leprosy and AIDS-related mycobacterial infections (Maggi et al., 1966;Ramos-e-Silva & Rebello, 2001;Sepkowitz et al., 1995). The potent antibacterial activity of this class of antibiotics is due to their specific inhibition of bacterial DNA-dependent RNA polymerases (Campbell et al., 2001;Wehrli & Staehelin, 1969). At the same time, they have relatively low if any activity against eukaryotic RNA polymerases. Due to their high selectivity for their molecular target, the rifamycins have become a safe and effective medication. Unfortunately, as with many other antibiotics, the incidence of resistance of Mycobacterium tuberculosis, the causative agent of tuberculosis, to rifamycins is continuing to increase over time, due largely to mutational alterations of the target molecule, the b subunit of RNA polymerase (Kirschbaum & Gotte, 1993;Suzuki et al., 1995). This high-level resistance has contributed to the recent reemergence of tuberculosis as a major health problem and the consequent increase in the death toll among world populations (Dye et al., 2002). Therefore, new drug discovery and continued development of the existing drugs to combat tuberculosis is indispensable.Despite the preparation of a large number of rifamycin derivatives by semi-synthetic approaches, the structural modifications have been limited primarily to one region of the molecule, the C-3 or C-4 positions of the aromatic core unit (Cricchio et al., 1974(Cricchio et al., , 1975Maggi et al., 1965; Wehrli et al., 1987). Alterations at other locations are difficult to accomplish chemically due to the complexity of the molecule, and require the implementation of alternative methodology, including combinatorial biosynthesis or mutasynthesis, to achieve additional...

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“…Mass spectral data of RIP-Ma (6) and RIP-Mb (7). 73.2ppm (C-2'), 71.7ppm (C-3'), 86.7ppm (C-4') and 63.5ppm (C-5'), that were absent in the spectra of rifampicin (1). Down field shifts ofH-23 (Adn 0.13 ppm) and C-23 signal (Adc 9.7ppm) of 7 relative to those of rifampiein indicated the ribosylation of the OHgroup on C-23.…”

Section: Structure Determinationmentioning

confidence: 95%