Studies on Novel Bacterial Translocase I Inhibitors, A-500359s. III. Deaminocaprolactam Derivatives of Capuramycin: A-500359 E, F, H, M-1 and M-2.

Muramatsu, Yasunori; Miyakoshi, Shunichi; Ogawa, Yasumasa; Ohnuki, Takashi; Ishii, Megumi; Arai, Masatoshi; Takatsu, Toshio; Inukai, Masatoshi

doi:10.7164/antibiotics.56.259

Cited by 35 publications

(23 citation statements)

References 3 publications

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“…4A). The CapP product was also tested for the ability to inhibit E. coli MraY activity in vitro using a previously developed fluorescence-based assay (7). Activity of MraY with varying amounts of A-503083 B (0.0016 -25 g/ml) yielded an IC 50 ϭ 0.0046 g/ml (ϳ8 nM) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…were prepared as described previously (7). The measurement of MraY inhibitory activity was performed in a 96-well plate in a total volume of 100 l containing 100 mM Tris-HCl (pH 7.5), 50 mM KCl, 25 mM MgCl 2 , 0.8% Triton X-100, 166 mM undecaprenyl phosphate,…”

Section: Methodsmentioning

confidence: 99%

“…1), the 3Ј-O-demethyl analogues of A-500359 A and B, termed A-500359 G and A-500359 C, respectively, and the deshydroxy analogue of A-500359 B, termed A-500359 D (6). Subsequently, a variety of deaminocaprolactam analogues were isolated upon feeding 2-aminoethyl-l-cysteine, a specific inhibitor of aspartokinase involved in lysine biosynthesis in actinomycetes, including the free acid A-500359 F and the methyl ester A-500359 E (8). Following the discovery of A-500359s, four capuramycin-type antibiotics named A-503083s were isolated from a different Streptomyces strain, and structural analysis revealed that, unlike the A-500359s, the A-503083s contain an additional 2Ј-O-carbamoyl group that slightly decreases the MraY inhibitory activity by 2-8-fold (9).…”

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confidence: 99%

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Functional and Kinetic Analysis of the Phosphotransferase CapP Conferring Selective Self-resistance to Capuramycin Antibiotics

Yang

Funabashi

Nonaka

et al. 2010

Journal of Biological Chemistry

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Capuramycin-related compounds, including A-500359s and A-503083s, are nucleoside antibiotics that inhibit the enzyme bacterial translocase I involved in peptidoglycan cell wall biosynthesis. Within the biosynthetic gene cluster for the A-500359s exists a gene encoding a putative aminoglycoside 3-phosphotransferase that was previously demonstrated to be highly expressed during the production of A-500359s and confers selective resistance to capuramycins when expressed in heterologous hosts. A similar gene (capP) was identified within the biosynthetic gene cluster for the A-503083s, and CapP is now shown to similarly confer selective resistance to capuramycins. Recombinant CapP was produced and purified from Escherichia coli, and the function of CapP is established as an ATP-dependent capuramycin phosphotransferase that regio-specifically transfers the ␥-phosphate to the 3؆-hydroxyl of the unsaturated hexuronic acid moiety of A-503083 B. Kinetic analysis with the three major A-503083 congeners suggests that CapP preferentially phosphorylates A-503083s containing an aminocaprolactam moiety attached to the hexuronic acid, and bi-substrate kinetic analysis was consistent with CapP employing a sequential kinetic mechanism similar to most known aminoglycoside 3-phosphotransferases. The purified CapP product lost its antibiotic activity against Mycobacterium smegmatis, and this loss in bioactivity is primarily due to a 272-fold increase in the IC 50 in the bacterial translocase I-catalyzed reaction. The results establish CapP-mediated phosphorylation as a mechanism of resistance to capuramycins and now set the stage to explore this strategy of resistance as a potential mechanism inherent to pathogens and provide the impetus for preparing second generation analogues as a preemptive strike to such resistance strategies.Infectious and parasitic diseases are the second leading cause of death worldwide, and this includes more than 1.6 million deaths by tuberculosis (TB) 4 in 2006 (1). Alarmingly, nearly 5% of all of the new cases of TB during this same year were caused by Mycobacterium tuberculosis, the primary causative agent of TB, that had resistance to at least one of the commonly used antibiotics to treat TB (2). To compound this problematic emergence of drug resistance, the discovery and development of new antibiotics have continued to decline with only a few new classes of antibiotics introduced into the clinic within the past few decades (3, 4). Thus, there is a great need for new antibiotics with novel modes of action and unique structures to combat multiple drug-resistant pathogens such as M. tuberculosis.Capuramycin was discovered from Streptomyces griseus 446-S3 based on gross antibacterial activity (5), and analogues termed A-500359s from S. griseus SANK 60196 (6 -8) and A-503083s from Streptomyces sp. SANK 62799 (9) were subsequently discovered using a specific screen aimed at identifying bacterial translocase I (MraY) inhibitors. MraY initiates the lipid cycle of peptidoglycan cell wall biosynthesis, a pathway ...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Functional and Kinetic Analysis of the Phosphotransferase CapP Conferring Selective Self-resistance to Capuramycin Antibiotics

Yang

Funabashi

Nonaka

et al. 2010

Journal of Biological Chemistry

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“…[10]. In the previous studies of capuramycin and A-500359s [10,11], we revealed the core skeleton (2Ј-methoxyuridine attached an unsaturated uronic acid moiety) was necessary for the inhibition of translocase I. Compared with the structure of A-102395, the core skeleton (partial structure A) is the same as of capuramycin, but A-102395 has the benzene with a uniquely substituted chain instead of an aminocaprolactam.…”

Section: Biological Activities Of A-102395mentioning

confidence: 99%

A-102395, a New Inhibitor of Bacterial Translocase I, Produced by Amycolatopsis sp. SANK 60206

et al. 2007

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Bacterial phospho-N-acetylmuramyl-pentapeptide translocase (translocase I: EC 2.7.8.13) is a key enzyme in peptidoglycan biosynthesis, and a known target of antibiotics. Here we report a new nucleoside inhibitor for translocase I, A-102395, isolated from the culture broth of the strain Amycolatopsis sp. SANK 60206. A-102395 is a new derivative of capuramycin that has the benzene with a uniquely substituted chain instead of an aminocaprolactam. A-102395 is a potent inhibitor of bacterial translocase I with IC 50 value of 11 nM, but possesses no antimicrobial activity against various strains tested.

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“…Peptidoglycan is essential and specific for bacteria; therefore, an antibiotic with translocase I inhibitory activity was expected to be appropriate for therapeutic use, especially against Staphylococcus aureus, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. So far, eight derivatives of A-500359s have been isolated and reported by Muramatsu et al (2003aMuramatsu et al ( , 2003b. A-500359s mainly comprise three parts, including uridine, sugar, and a caprolactam ring.…”

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An Investigation of Regulatory Mechanisms of A-500359s Production in Mutants Isolated from Streptomyces griseus SANK 60196

et al. 2009

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The nucleoside antibiotic A-500359s are produced by Streptomyces griseus SANK 60196. During a screening program of A-500359s high-producing strains, several interesting mutants were isolated and classified into three groups according to two characteristics, spore-forming ability and the retention of a giant linear plasmid SGF180, as follows: , . A-500359s production was markedly decreased in all the mutants and completely lacking in all the baldtype mutants. To understand the regulatory mechanisms of A-500359s production in these mutants, co-cultivation analyses were conducted in several mutant combinations, and the effect of an addition of an EtOAc extract, which was prepared from a culture broth of an A-500359s producer, was tested. A-500359s production was clearly restored when mutant [spore+ SGF180-] was co-cultivated with mutant [bald SGF180+] and the A-500359s production of the mutant [bald SGF180+] was activated by the addition of an EtOAc extract. The results suggested that SGF180 plays an important role in A-500359s production and that A-500359s biosynthesis might be controlled by a low molecular weight compound, such as an A-factor-like compound, synthesized by the product of afsA gene that was lost in all the tested bald-type mutants.A-500359s were discovered in a culture broth of Streptomyces griseus SANK 60196 as members of the translocase I inhibitors (Muramatsu et al., 2003a). Translocase I is an enzyme that catalyzes the first step in the lipid cycle of peptidoglycan biosynthesis. Peptidoglycan is essential and specific for bacteria; therefore, an antibiotic with translocase I inhibitory activity was expected to be appropriate for therapeutic use, especially against Staphylococcus aureus, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. So far, eight derivatives of A-500359s have been isolated and reported by Muramatsu et al. (2003aMuramatsu et al. ( , 2003b. A-500359s mainly comprise three parts, including uridine, sugar, and a caprolactam ring. The origin of the A-500359s structures was determined and reported by Ohnuki et al. (2003). In addition, culture conditions and media compositions suitable for their production were studied with a view toward commercialization (Muramatsu et al., 2006). During a screening program of A-500359s high-producing strains, a high producer, named strain HP, was isolated by random mutation. Strain HP was treated at a high temperature for further screening to isolate higher producing strains. Strain HP was cultured in Trypto Soy Broth (TSB) medium for seven days at 35, 37, or 39 C. After several rounds of high temperature treatment, six strains (strains 35-1, 35-2, 37-2, 37-3, 37-4, and 37-6) were isolated as spore-forming strains and four mutants (mutants 35-4, 37-9, 39-5 and 39-6) were isolated as bald-type mutants. These isolated strains were cultured in a test tube containing 5 ml of PM-1 medium (Muramatsu et al., 2006) for three days at 23 C. One ml of the resulting culture broth was transferred into a 100 ml Erlenmeyer flask containing 20 ml of OM-1 m...

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Studies on Novel Bacterial Translocase I Inhibitors, A-500359s. III. Deaminocaprolactam Derivatives of Capuramycin: A-500359 E, F, H, M-1 and M-2.

Cited by 35 publications

References 3 publications

Functional and Kinetic Analysis of the Phosphotransferase CapP Conferring Selective Self-resistance to Capuramycin Antibiotics

Functional and Kinetic Analysis of the Phosphotransferase CapP Conferring Selective Self-resistance to Capuramycin Antibiotics

A-102395, a New Inhibitor of Bacterial Translocase I, Produced by Amycolatopsis sp. SANK 60206

An Investigation of Regulatory Mechanisms of A-500359s Production in Mutants Isolated from Streptomyces griseus SANK 60196

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