Divalent metal ion catalysis of the oxidation of rifamycin SV to refamycin S

Scrutton, Michael C.

doi:10.1016/0014-5793(77)80309-8

Cited by 12 publications

(3 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(Supplementary Fig. 6 ), similar to previously reported findings 23 . However, we cannot exclude the possibility that an oxidase might be responsible for enzymatic oxidation of R-SV into R-S in vivo.…”

Section: Resultssupporting

confidence: 92%

Deciphering the late steps of rifamycin biosynthesis

Zhang

et al. 2018

Nat Commun

View full text Add to dashboard Cite

Rifamycin-derived drugs, including rifampin, rifabutin, rifapentine, and rifaximin, have long been used as first-line therapies for the treatment of tuberculosis and other deadly infections. However, the late steps leading to the biosynthesis of the industrially important rifamycin SV and B remain largely unknown. Here, we characterize a network of reactions underlying the biosynthesis of rifamycin SV, S, L, O, and B. The two-subunit transketolase Rif15 and the cytochrome P450 enzyme Rif16 are found to mediate, respectively, a unique C–O bond formation in rifamycin L and an atypical P450 ester-to-ether transformation from rifamycin L to B. Both reactions showcase interesting chemistries for these two widespread and well-studied enzyme families.

show abstract

Section: Resultssupporting

confidence: 92%

Deciphering the late steps of rifamycin biosynthesis

Zhang

et al. 2018

Nat Commun

View full text Add to dashboard Cite

show abstract

“…This proximity, coupled with the reported ability of rifamycin to cycle between a radical and non-radical form (rifamycin SV and rifamycin S52, 53), may damage DNA through a direct drug-DNA interaction. This hypothesis may account for the observation that rifamycin SV can induce the SOS DNA damage response in E. coli , and that treatment of recA E. coli results in cell death whereas treatment of wildtype E. coli leads to bacteriostasis8.…”

Section: Inhibition Of Rna Synthesis By Rifamycinsmentioning

confidence: 99%

How antibiotics kill bacteria: from targets to networks

2010

View full text Add to dashboard Cite

PrefaceAntibiotic drug-target interactions, and their respective direct effects, are generally wellcharacterized. In contrast, the bacterial responses to antibiotic drug treatments that contribute to cell death are not as well understood and have proven to be quite complex, involving multiple genetic and biochemical pathways. Here, we review the multi-layered effects of drug-target interactions, including the essential cellular processes inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing by bactericidal antibiotics. We also discuss new insights into these mechanisms that have been revealed through the study of biological networks, and describe how these insights, together with related developments in synthetic biology, may be exploited to create novel antibacterial therapies. IntroductionOur understanding of how antibiotics induce bacterial cell death is centered on the essential cellular function inhibited by the primary drug-target interaction. Antibiotics can be classified based on the cellular component or system they affect, in addition to whether they induce cell death (bactericidal drugs) or merely inhibit cell growth (bacteriostatic drugs). Most current bactericidal antimicrobials, which are the focus of this review, inhibit DNA synthesis, RNA synthesis, cell wall synthesis, or protein synthesis 1 .Since the discovery of penicillin was reported in 1929 2 , other, more effective antimicrobials have been discovered and developed by elucidation of drug-target interactions, and by drug molecule modification. These efforts have significantly enhanced our clinical armamentarium. Antibiotic-mediated cell death, however, is a complex process that begins with the physical interaction between a drug molecule and its bacterial-specific target, and involves alterations to the affected bacterium at the biochemical, molecular and ultrastructural levels. The increasing prevalence of drug-resistant bacteria 3 , as well as the means of gaining resistance, has made it crucial that we better understand the multilayered mechanisms by which currently available antibiotics kill bacteria, as well as explore and find alternative antibacterial therapies.Antibiotic-induced cell death has been associated with the formation of double-stranded DNA breaks following treatment with DNA gyrase inhibitors 4 , with the arrest of DNA-dependent RNA synthesis following treatment with rifamycins 5 , with cell envelope damage and loss of structural integrity following treatment with cell-wall synthesis inhibitors 6 , and with cellular energetics, ribosome binding and protein mistranslation following treatment with protein * Corresponding author: James Collins, jcollins@bu.edu, phone: (617) 353-0390. NIH Public Access Author ManuscriptNat Rev Microbiol. Author manuscript; available in PMC 2010 December 1. Published in final edited form as:Nat Rev Microbiol. 2010 June ; 8(6): 423-435. doi:10.1038/nrmicro2333. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sy...

show abstract

“…Both the hydroquinone moiety and the long aliphatic bridge of rifamycin SV are responsible for its pharmacochemical behaviour. Rifamycin SV can undergo autoxidation when exposed to air for a long period of time (Scrutton, 1977;Kono, 1982). This aerobic oxidation is accelerated by certain metals (Kono, 1982).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of NADH-dependent microsomal DNA strand cleavage by rifamycin SV

Kukielka

Cederbaum

1995

Biochemical Journal

View full text Add to dashboard Cite

Rifamycin SV is an antibiotic anti-bacterial agent used in the treatment of tuberculosis. This drug can autoxidize, especially in the presence of metals, and generate reactive oxygen species. A previous study indicated that rifamycin SV can increase NADH-dependent microsomal production of reactive oxygen species. The current study evaluated the ability of rifamycin SV to interact with iron and increase microsomal production of hydroxyl radical, as detected by conversion of supercoiled plasmid DNA into the relaxed open circular state. The plasmid used was pBluescript II KS(-), and the forms of DNA were separated by agarose-gel electrophoresis. Incubation of rat liver microsomes with plasmid plus NADH plus ferric-ATP caused DNA strand cleavage. The addition of rifamycin SV produced a time- and concentration-dependent increase in DNA-strand cleavage. No stimulation by rifamycin SV occurred in the absence of microsomes, NADH or ferric-ATP. Stimulation occurred with other ferric complexes besides ferric-ATP, e.g. ferric-histidine, ferric-citrate, ferric-EDTA, and ferric-(NH4)2SO4. Rifamycin SV did not significantly increase the high rates of DNA strand cleavage found with NADPH as the microsomal reductant. The stimulation of NADH-dependent microsomal DNA strand cleavage was completely blocked by catalase, superoxide dismutase, GSH and a variety of hydroxyl-radical-scavenging agents, but not by anti-oxidants that prevent microsomal lipid peroxidation. Redox cycling agents, such as menadione and paraquat, in contrast with rifamycin SV, stimulated the NADPH-dependent reaction; menadione and rifamycin SV were superior to paraquat in stimulating the NADH-dependent reaction. These results indicate that rifamycin SV can, in the presence of an iron catalyst, increase microsomal production of reactive oxygen species which can cause DNA-strand cleavage. In contrast with other redox cycling agents, the stimulation by rifamycin SV is more pronounced with NADH than with NADPH as the microsomal reductant. Interactions between rifamycin SV, iron and NADH generating hydroxyl-radical-like species may play a role in some of the hepatotoxic effects associated with the use of this antibacterial antibiotic.

show abstract

Divalent metal ion catalysis of the oxidation of rifamycin SV to refamycin S

Cited by 12 publications

References 4 publications

Deciphering the late steps of rifamycin biosynthesis

Deciphering the late steps of rifamycin biosynthesis

How antibiotics kill bacteria: from targets to networks

Stimulation of NADH-dependent microsomal DNA strand cleavage by rifamycin SV

Contact Info

Product

Resources

About