New rifamycins modified at positions 3 and 4. Synthesis, structure and biological evaluation.

Marsili, L; Pasqualucci, C.R.; Vigevani, A.; Gioia, B.; Schioppacassi, G; Oronzo, Giuliano

doi:10.7164/antibiotics.34.1033

Cited by 33 publications

(21 citation statements)

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“…Rifabutin (RFB) is a semisynthetic derivative of rifamycin S and, together with RIF, is part of the rifamycin family (2). Both RIF and RFB inhibit mycobacterial growth by blocking the DNAdependent RNA polymerase subunit B (RpoB) (3,4).…”

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Profiling of rpoB Mutations and MICs for Rifampin and Rifabutin in Mycobacterium tuberculosis

et al. 2014

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bResistance to rifampin (RIF) and rifabutin (RFB) in Mycobacterium tuberculosis is associated with mutations within an 81-bp region of the rpoB gene (RIF resistance-determining region [RRDR]). Previous studies have shown that certain mutations in this region are more likely to confer high levels of RIF resistance, while others may be found in phenotypically susceptible isolates. In this study, we sought to determine the relationship between the MICs of RIF and RFB and rpoB RRDR mutations in 32 multidrug-resistant (MDR), 4 RIF-monoresistant, and 5 susceptible M. tuberculosis clinical isolates. The MICs were determined using the MGIT 960 system. Mutations in the rpoB RRDR were determined by Sanger sequencing. RpoB proteins with mutations S531L (a change of S to L at position 531), S531W, H526Y, and H526D and the double mutation D516A-R529Q were associated with high MICs for RIF and RFB. Five isolates carrying the mutations L511P, H526L, H526N, and D516G-S522L were found to be susceptible to RIF. Several mutations were associated with resistance to RIF and susceptibility to RFB (F514FF, D516V, and S522L). Whole-genome sequencing of two MDR isolates without rpoB RRDR mutations revealed a mutation outside the RRDR (V146F; RIF MIC of 50 g/ml). The implications of the polymorphisms identified in the second of these isolates in RIF resistance need to be further explored. Our study further establishes a correlation between the mutations and the MICs of RIF and, also, RFB in M. tuberculosis. Several rpoB mutations were identified in RIF-and RFB-susceptible isolates. The clinical significance of these findings requires further exploration. Until then, a combination of phenotypic and molecular testing is advisable for drug susceptibility testing.

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Profiling of rpoB Mutations and MICs for Rifampin and Rifabutin in Mycobacterium tuberculosis

et al. 2014

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“…Rifabutin (ansamycin; LM427) is a semisynthetic rifamycin similar in structure and activity to rifampin (7). In addition to in vitro activity against a variety of gram-negative and gram-positive organisms, it also has activity against Mycobacterium tuberculosis and Mycobacterium avium complex (4,9).…”

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Pharmacokinetics of rifabutin

Skinner

Hsieh

Torseth

et al. 1989

Antimicrob Agents Chemother

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We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled ['4C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 + 2% (mean + standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.Rifabutin (ansamycin; LM427) is a semisynthetic rifamycin similar in structure and activity to rifampin (7). In addition to in vitro activity against a variety of gram-negative and gram-positive organisms, it also has activity against Mycobacterium tuberculosis and Mycobacterium avium complex (4, 9). Recent in vitro studies have shown 92% inhibition of reverse transcriptase activity in human immunodeficiency virus-infected lymphocytes when used at a concentration of 0.1 .g/ml (1). As part of a phase I study of rifabutin in patients with early symptomatic human immunodeficiency virus infections, we studied the pharmacokinetics of rifabutin in patients with acquired immunodeficiency syndrome-related complex at four different dosage levels: 300, 600, 900, and 1,200 mg/day. MATERIALS AND METHODSSubjects. Fifteen male patients, ages 28 to 44 years, with early symptomatic human immunodeficiency virus infections were studied after giving informed consent. All patients had either oral thrush or chronic lymphadenopathy but were otherwise in generally good health. Patients were excluded when they had evidence of impaired renal (creatinine clearance of <85% of expected value based on Cockcroft-Gault equation) or hepatic (serum glutamic oxalacetic transaminase or serum glutamic pyruvic transaminase of >60 or bilirubin of >1.2 mg/100 ml) function, known hypersensitivity to rifabutin or rifampin, or recent use of other antiviral agents or immunomodulating agents or of cytolytic or other agents for cancer treatment. All nonessential medications were discontinued prior to enrollment in the trial. Patients were allowed...

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“…Ansamycin is a derivative of rifamycin SV (4,7,12). Its in vitro activity against Mycobacterium avium complex was reported by Woodley and Kilburn (21), Ungheri et al (20), Cynamon (3), and Heifets and Iseman (5).…”

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Two Groups of Mycobacterium avium Complex Strains Determined According to the Susceptibility to Rifampicin and Ansamycin

Tsukamura

1987

Microbiology and Immunology

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Mycobacterium avium complex strains previously not exposed to any antituberculosis agents could be divided into two groups according to their susceptibility to rifampicin and ansamycin; one group susceptible to 80 ,ugiml rifampicin and to 1.25 ,ugiml ansamycin, and another resistant to these concentrations. In each group, the ratio of the minimal inhibitory concentration of ansamycin against that of rifampicin was greatly different depending on the strain. This naturally occurring resistance to rifampicin and ansamycin was frequently correlated to naturally occurring resistance to ethambutol, kanamycin, enviomycin, kitasamycin, and minocycline, but not correlated to that to isoniazid and sulfadimethoxine. Ansamycin was more active than rifampicin against M. bovis, M. kansasii, M. marinum, M. xenopi, and M. haemophilum.Ansamycin is a derivative of rifamycin SV (4, 7, 12). Its in vitro activity against Mycobacterium avium complex was reported by Woodley and Kilburn (21), Ungheri et al (20), Cynamon (3), and Heifets and Iseman (5). It inhibited the growth of the M. avium complex strains at concentrations of 1 to 2 ,ug/ml in the 7H-10 agar, 7H-10 broth, or 7H-11 agar medium (3,5,20,21). Therefore, ansamycin is at present the most promising agent for the treatment of disease due to the M. avium complex, which is resistant to most antituberculosis agents. However, the cross-resistance relationship between rifampicin and ansamycin (both are derivatives of rifamycin SV) is not yet clear. Employing the 7H-11 agar medium, Heifets and Iseman (5) reported that all strains that were susceptible to 1.0 ,ug/ml rifampicin were susceptible to 0.5 ,ug/ml ansamycin and 20% of the strains, which were naturally resistant to 10 dug/ml rifampicin, were susceptible to 0.5 iug/ml ansamycin. Only 10% of the latter strains were resistant to 2.0 eug/ml ansamycin. Their finding suggests that the cross-resistance relationship between these two agents is only partial. The present study has been carried out to clarify the cross-resistance relationship. 615

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New rifamycins modified at positions 3 and 4. Synthesis, structure and biological evaluation.

Cited by 33 publications

References 4 publications

Profiling of rpoB Mutations and MICs for Rifampin and Rifabutin in Mycobacterium tuberculosis

Profiling of rpoB Mutations and MICs for Rifampin and Rifabutin in Mycobacterium tuberculosis

Pharmacokinetics of rifabutin

Two Groups of Mycobacterium avium Complex Strains Determined According to the Susceptibility to Rifampicin and Ansamycin

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