Lipiarmycin, a new antibiotic from Actinoplanes. III. Mechanism of action.

Sergio, S Rozenel; Pirali, G.; White, Richard; Parenti, Francesco

doi:10.7164/antibiotics.28.543

Cited by 67 publications

(45 citation statements)

References 3 publications

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“…Fidaxomicin is the generic name of an Actinoplanes product, variously known as lipiarmycin (Table 4), tiacumicin B, and difimicin, discovered in 1975 (289). It is a specific inhibitor of transcription by RNA polymerase (328,344), and in B. subtilis, it selects for resistant mutants mapping in rpoC (at a frequency of 2 ϫ 10 Ϫ6 in one report [344] and Ͻ10 Ϫ7 in another [although 2 such mutants were indeed selected and mapped] [142]). Such mutants have MICs that are raised Ն16-fold.…”

Section: Enoyl-reductases Of Fas II the Enoyl-reductases Of Bacteriamentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,138

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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Section: Enoyl-reductases Of Fas II the Enoyl-reductases Of Bacteriamentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,138

961

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“…la). This compound is apparently identical to one of the lipiarmycins, a previously described group of antibiotics produced by Actinoplanes deccanensis (1,10,12), and to clostomicin Bi, an antibiotic from Micromonospora echinospora (9). Tiacumicin C differs in the position of butyrate esterification on the seven-carbon sugar (Fig.…”

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confidence: 99%

In vitro and in vivo evaluation of tiacumicins B and C against Clostridium difficile

Swanson

Hardy

Shipkowitz

et al. 1991

Antimicrob Agents Chemother

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Tiacumicins B and C are members of a novel group of 18-membered macrolide antibiotics with in vitro activity against Clostridium difficile. The MICs against 15 strains of C. difficile were 0.12 to 0.25 ,ug/mI for tiacumicin B, 0.25 to 1 ,ug/ml for tiacumicin C, and 0.5 to 1 ,ug/ml for vancomycin. The The tiacumicins are a group of 18-membered macrolide antibiotics originally isolated from the fermentation broth of Dactylosporangium aurantiacum subsp. hamdenensis (7,16). Tiacumicin B, the major antibiotic component produced by this culture, contains an unsaturated 18-membered macrolide ring with a seven-carbon sugar at carbon 11 and a 6-deoxy sugar at carbon 20 (Fig. la). This compound is apparently identical to one of the lipiarmycins, a previously described group of antibiotics produced by Actinoplanes deccanensis (1, 10, 12), and to clostomicin Bi, an antibiotic from Micromonospora echinospora (9). Tiacumicin C differs in the position of butyrate esterification on the seven-carbon sugar (Fig. lb). Tiacumicin C appears to be identical to clostomicin B2, a member of the clostomicin complex isolated from M. echinospora (9).A preliminary report on the biological properties of the tiacumicins indicated that tiacumicin B has moderate activity against pathogenic strains of Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecium and demonstrated that it has limited, but potent, activity against several anaerobic bacteria (16). In the same study, tiacumicin C was found to have a similar spectrum of activity but to be less potent than tiacumicin B.The present study was designed to examine the in vitro activities of the tiacumicins against Clostridium difficile and to evaluate the efficacies of these compounds in treating antibiotic-associated pseudomembranous colitis caused by * Corresponding author. In vitro potency. MICs in Wilkins-Chalgren agar were determined by a standard twofold agar dilution procedure (13).Effect of serum and pH on in vitro activity. The effects of 50% hamster serum and at pHs 6.5, 7.3, and 8.0 on the in vitro potencies of the tiacumicins in Wilkins-Chalgren broth were determined by a microdilution method (13). To separate the effect of pH from the effect of serum, the pHs of the serum samples were adjusted to 7.3 prior to testing.Effect of hamster cecal contents on in vitro activity. The bioavailabilities of the tiacumicins in the presence of normal hamster cecal contents were determined by a previously described methodology (13). Briefly, MICs and MBCs of

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“…Fidaxomicin (formerly OPT-80 or PAR-101) is a potent new macrocyclic antibiotic that targets RNA polymerase (21). The drug has a narrow spectrum of activity, with no activity against Gram-negative bacteria and many anaerobes but high activity against C. difficile (1,4,13,22).…”

mentioning

confidence: 99%

Comparative Susceptibilities to Fidaxomicin (OPT-80) of Isolates Collected at Baseline, Recurrence, and Failure from Patients in Two Phase III Trials of Fidaxomicin against Clostridium difficile Infection

Goldstein¹,

Citron²,

Sears³

et al. 2011

Antimicrob Agents Chemother

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A total of 65 (7.9%) "rifaximin-resistant" (MIC > 256 g/ml) strains were isolated in both treatment groups on enrollment, which increased to 25% for failures at the end of therapy. No resistance to either fidaxomicin or vancomycin developed during treatment in either of the phase III studies, although a single strain isolated from a cured patient had an elevated fidaxomicin MIC of 16 g/ml at the time of recurrence. All isolates were susceptible to <4 g/ml of metronidazole. When analyzed by restriction endonuclease analysis (REA) type, 247/719 (34.4%) isolates were BI group isolates, and the MICs were generally higher for all four drugs tested (MIC 90 s: fidaxomicin, 0.5; vancomycin, 2.0; metronidazole, 2.0; and rifaximin, >256 g/ml) than for the other REA types. There was no correlation between the MIC of a baseline clinical isolate and clinical outcome. MIC 90 s were generally low for fidaxomicin and vancomycin, but BI isolates had higher MICs than other REA group isolates.

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Lipiarmycin, a new antibiotic from Actinoplanes. III. Mechanism of action.

Cited by 67 publications

References 3 publications

Challenges of Antibacterial Discovery

Challenges of Antibacterial Discovery

In vitro and in vivo evaluation of tiacumicins B and C against Clostridium difficile

Comparative Susceptibilities to Fidaxomicin (OPT-80) of Isolates Collected at Baseline, Recurrence, and Failure from Patients in Two Phase III Trials of Fidaxomicin against Clostridium difficile Infection

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