Pentamidine inhibits mitochondrial intron splicing and translation in Saccharomyces cerevisiae

Zhang, Yi; Bell, Adam C.; Perlman, Philip S.; Leibowitz, Michael J.

doi:10.1017/s1355838200991726

Cited by 46 publications

(38 citation statements)

References 65 publications

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“…Another exciting avenue for further investigation is the potential for using self-splicing introns as antimicrobial targets to treat Q fever. For example, pentamidine, a drug used for the treatment and prophylaxis of Pneumocystis carinii (Pneumocystis jiroveci) pneumonia (16), is thought to act by inhibiting rRNA group I intron self-splicing (42). Although pentamidine has toxic side effects, it might be a potential therapeutic agent for treating patients with chronic Q fever endocarditis.…”

Section: Discussionmentioning

confidence: 99%

The Unusual 23S rRNA Gene of Coxiella burnetii : Two Self-Splicing Group I Introns Flank a 34-Base-Pair Exon, and One Element Lacks the Canonical ΩG

et al. 2007

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We describe the presence and characteristics of two self-splicing group I introns in the sole 23S rRNA gene of Coxiella burnetii. The two group I introns, Cbu.L1917 and Cbu.L1951, are inserted at sites 1917 and 1951 (Escherichia coli numbering), respectively, in the 23S rRNA gene of C. burnetii. Both introns were found to be self-splicing in vivo and in vitro even though the terminal nucleotide of Cbu.L1917 is adenine and not the canonical conserved guanine, termed ⍀G, found in Cbu.L1951 and all other group I introns described to date. Predicted secondary structures for both introns were constructed and revealed that Cbu.L1917 and Cbu.L1951 were group IB2 and group IA3 introns, respectively. We analyzed strains belonging to eight genomic groups of C. burnetii to determine sequence variation and the presence or absence of the elements and found both introns to be highly conserved (>99%) among them. Although phylogenetic analysis did not identify the specific identities of donors, it indicates that the introns were likely acquired independently; Cbu.L1917 was acquired from other bacteria like Thermotoga subterranea and Cbu.L1951 from lower eukaryotes like Acanthamoeba castellanii. We also confirmed the fragmented nature of mature 23S rRNA in C. burnetii due to the presence of an intervening sequence. The presence of three selfish elements in C. burnetii's 23S rRNA gene is very unusual for an obligate intracellular bacterium and suggests a recent shift to its current lifestyle from a previous niche with greater opportunities for lateral gene transfer.Group I introns are a distinct class of catalytic RNAs (ribozymes) that are considered a legacy of a primordial RNA world (40). They are able to self-splice by means of a two-step transesterification reaction using a guanosine molecule as a cofactor. The catalytic structure that is conserved among all group I introns consists of a specific arrangement of about 10 paired elements (P) that are capped by loops and connected by junctions (J) (38). The core of each intron is comprised of two separately folding helical domains made up of P4-P5-P6 and P3-P7-P9. The P4-P6 domain structurally supports the P3-P9 domain, which contains the active site (17). Splice sites are determined by helix P1, which pairs with the 5Ј substrate strand (5Ј exon), and by helix P10, which pairs with the 3Ј substrate strand (3Ј exon). A conserved G · U wobble pair contributes to the recognition of the 5Ј splice site, whereas the 3Ј splice site is recognized in part by a conserved terminal guanine, termed ⍀G (23). Based on conserved secondary-structure characteristics, group I introns are further classified into 13 subgroups (23, 34). These selfish genetic elements are distributed widely in nature, albeit with a bias towards fungi, plants, and red or green algae (14). Although group I introns are abundant in mitochondria and chloroplasts of lower eukaryotes, they are relatively rare in bacteria and until recently were unknown in bacterial structural RNAs. Group I introns in 23S rRNA genes have been...

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Section: Discussionmentioning

confidence: 99%

The Unusual 23S rRNA Gene of Coxiella burnetii : Two Self-Splicing Group I Introns Flank a 34-Base-Pair Exon, and One Element Lacks the Canonical ΩG

et al. 2007

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“…Pentamidine is used mainly to treat AIDS-related Pneumocystis jirovecii pneumonia, the early stage of human African trypanosomiasis, and antimony-resistant leishmaniasis (7,22,26). It was reported that the mechanisms of action of pentamidine include inhibition of topoisomerase (2), binding to an AT-rich DNA minor groove (26), inhibition of splicing of group I and II introns (14,16,30), and collapse of mitochondrial function (13,15,18,30). Pafuramidine (DB289) has been developed as a prodrug of DB75 and has been demonstrated to have anti-Pneumocystis activity and antiparasitic activity against Plasmodium falciparum and Trypanosoma spp.…”

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T-2307 Causes Collapse of Mitochondrial Membrane Potential in Yeast

Shibata

Takahashi

Yamada

et al. 2012

Antimicrob Agents Chemother

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T-2307, an arylamidine compound, has been previously reported to have broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens, including Candida species, Cryptococcus neoformans, and Aspergillus species, and is now undergoing clinical trials. Here we investigated the mechanism of action of T-2307 using yeast cells and mitochondria isolated from yeast and rat liver. Nonfermentative growth of Candida albicans and Saccharomyces cerevisiae in glycerol medium, in which yeasts relied on mitochondrial respiratory function, was inhibited at 0.001 to 0.002 g/ml (0.002 to 0.004 M) of T-2307. However, fermentative growth in dextrose medium was not inhibited by T-2307. Microscopic examination using Mitotracker fluorescent dye, a cell-permeant mitochondrion-specific probe, demonstrated that T-2307 impaired the mitochondrial function of C. albicans and S. cerevisiae at concentrations near the MIC in glycerol medium. T-2307 collapsed the mitochondrial membrane potential in mitochondria isolated from S. cerevisiae at 20 M. On the other hand, in isolated rat liver mitochondria, T-2307 did not have any effect on the mitochondrial membrane potential at 10 mM. Moreover, T-2307 had little inhibitory and stimulatory effect on mitochondrial respiration in rat liver mitochondria. In conclusion, T-2307 selectively disrupted yeast mitochondrial function, and it was also demonstrated that the fungal mitochondrion is an attractive antifungal target.

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“…Pentamidine has been shown to be selectively bound in the minor groove of AT-rich DNA duplexes (5,10,18); however, its antimicrobial activities are not proven to be due to DNA binding (25). Pentamidine has also been demonstrated to inhibit the self-splicing of various group I introns in vitro, including the nuclear group I introns present in the rRNA genes of Pneumocystis carinii (13,14), the Ca.LSU nuclear group I intron in the 26S rRNA gene of Candida albicans (15), and the mitochondrial introns of S. cerevisiae (31).…”

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confidence: 99%

In Vitro and In Vivo Antifungal Activities of T-2307, a Novel Arylamidine

Mitsuyama

Nomura

Hashimoto

et al. 2008

Antimicrob Agents Chemother

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The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including Candida species (MIC range, 0.00025 to 0.0078 g/ml), Cryptococcus neoformans (MIC range, 0.0039 to 0.0625 g/ml), and Aspergillus species (MIC range, 0.0156 to 4 g/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent Candida albicans strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some Candida and Aspergillus species and against Cryptococcus neoformans. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg ⅐ kg ؊1 ⅐ dose ؊1 , respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.

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Pentamidine inhibits mitochondrial intron splicing and translation in Saccharomyces cerevisiae

Cited by 46 publications

References 65 publications

The Unusual 23S rRNA Gene of Coxiella burnetii : Two Self-Splicing Group I Introns Flank a 34-Base-Pair Exon, and One Element Lacks the Canonical ΩG

The Unusual 23S rRNA Gene of Coxiella burnetii : Two Self-Splicing Group I Introns Flank a 34-Base-Pair Exon, and One Element Lacks the Canonical ΩG

T-2307 Causes Collapse of Mitochondrial Membrane Potential in Yeast

In Vitro and In Vivo Antifungal Activities of T-2307, a Novel Arylamidine

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