Pseudomonic Acid: an Antibiotic produced by Pseudomonas fluorescens

Fuller, A. T.; Mellows, G.; Woolford, Michael K.; Banks, G. T.; Barrow, Kevin D.; Chain, E. B.

doi:10.1038/234416a0

Cited by 257 publications

(129 citation statements)

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“…1,2 It inhibits bacterial isoleucyl--transfer RNA syn--thetase and is currently the standard treatment used worldwide for the topical control of MRSA. 3 The major component of mupirocin is pseudomonic acid A (1, PA--A, Fig.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of Mupirocin by Pseudomonas fluorescens NCIMB 10586 Involves Parallel Pathways

Gao

Hothersall

et al. 2014

J. Am. Chem. Soc.

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Detailed metabolic profiling of mutant strains produced by systematic inactivation of PKS and tailoring genes, along with re--feeding of isolated metabo--lites to mutant stains, has allowed the isolation of a large number of novel metabolites, identification of the 10,11--epoxidase and the full characterisation of the mupirocin biosynthetic pathway which proceeds via major (10,11--epoxide) and minor (10,11--alkene) parallel pathways.

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Section: Introductionmentioning

confidence: 99%

Biosynthesis of Mupirocin by Pseudomonas fluorescens NCIMB 10586 Involves Parallel Pathways

Gao

Hothersall

et al. 2014

J. Am. Chem. Soc.

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“…These two inhibitors exhibit different modes of action with one targeting the aaRS synthetic site and the other targeting the editing site. Mupirocin (pseudomonic acid), naturally produced by Pseudomonas fluorescens , is a broad-spectrum competitive inhibitor that blocks the synthetic site of various bacterial IleRSs, but not that of the human enzyme [7,8]. This compound is currently used as a topical ointment to treat various skin infections including impetigo and methicillin-resistant Staphylococcus aureus (MRSA) [9-11].…”

Section: Introductionmentioning

confidence: 99%

A continuous assay for monitoring the synthetic and proofreading activities of multiple aminoacyl-tRNA synthetases for high-throughput drug discovery

Grube

Roy

2017

RNA Biology

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Aminoacyl-tRNA synthetases (aaRSs) catalyze the aminoacylation of tRNAs to produce the aminoacyl-tRNAs (aa-tRNAs) required by ribosomes for translation of the genetic message into proteins. To ensure the accuracy of tRNA aminoacylation, and consequently the fidelity of protein synthesis, some aaRSs exhibit a proofreading (editing) site, distinct from the aa-tRNA synthetic site. The aaRS editing site hydrolyzes misacylated products formed when a non-cognate amino acid is used during tRNA charging. Because aaRSs play a central role in protein biosynthesis and cellular life, these proteins represent longstanding targets for therapeutic drug development to combat infectious diseases. Most existing aaRS inhibitors target the synthetic site, and it is only recently that drugs targeting the proofreading site have been considered. In the present study, we developed a robust assay for the high-throughput screening of libraries of inhibitors targeting both the synthetic and the proofreading sites of up to four aaRSs simultaneously. Thus, this assay allows for screening of eight distinct enzyme active sites in a single experiment. aaRSs from several prominent human pathogens (i.e., Mycobacterium tuberculosis, Plasmodium falciparum, and Escherichia coli) were used for development of this assay.

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“…A relaxation delay (RD) of 10 to 20 seconds was used depending upon whether the non-protonated carbons were being studied or not. The T1's were determined by fitting the experimental signal intensity data to equation [1] .. . I=10-A.e-VD/T1 [1] .…”

mentioning

confidence: 99%

“…The T1's were determined by fitting the experimental signal intensity data to equation [1] .. . I=10-A.e-VD/T1 [1] . …”

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Segmental motion in pseudomonic acid A: A carbon-13 spin-lattice relaxation time study at two field strengths.

Everett

Tyler

1984

J. Antibiot.

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The mobility of pseudomonic acid A in dimethyl sulfoxide-d3 solution has been determined from 13C spin-lattice relaxation time measurements at two field strengths. The central tetrahydropyran ring reorientates isotropically with a rotational correlation time of -280 picoseconds/radian.Both side-chains exhibit marked segmental motion with correlation times decreasing to only -50 picoseconds/radian at the end of the nonanoic acid side-chain.Pseudomonic acid A is a naturally occurring antibiotic produced by fermentation of a strain of Pseudomonas flourescens.l" The gross structure was elucidated on the basis of spectroscopic and degradative data.'' This structure was confirmed and the absolute stereochemistry shown to be I by further spectroscopic and X-ray work.3)We have now measured the 13C spin-lattice relaxation times (T1's) of all the carbon atoms in I in order to gain information about the mobility of I in solution. This information is potentially useful in the understanding of both the biological activity of I and also the interaction of I with other molecules and ions in solution. The T1 data has also served as a check on the 13C spectral assignments.Results Table 1 gives the 20 MHz 13C T1 and nuclear overhauser effect (NOE) results, the 63 MHz 13C T1and NOE results and the effective 13C correlation times for a dimethyl sulfoxide-de solution of I. Fig. 1 shows three partially relaxed 63 MHz 13C spectra of I in dimethyl sulfoxide-de. ExperimentalAll experiments were conducted at ambient temperature on -0.6 M solutions of pseudomonic acid A in DMSO-de. The 20 MHz 13C NMR data was acquired on a Bruker WP 80 using 10 mm tubes. The sweep width was 3787.9 Hz over 8 K data points.The 90° pulse for 13C was -17 pseconds. The free induction decays (FIDs) were zero-filled to 16 K points and a line broadening of 1 to 1.5 Hz was applied prior to Fourier transformation.The 63 MHz 13C data was acquired on a Bruker WM250 using 5 mm tubes in a 13C/1H dual probe.The sweep width was 11627.9 Hz over 16 K data points. The 90° pulse for 13C was -10 lrseconds.

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Pseudomonic Acid: an Antibiotic produced by Pseudomonas fluorescens

Cited by 257 publications

References 0 publications

Biosynthesis of Mupirocin by Pseudomonas fluorescens NCIMB 10586 Involves Parallel Pathways

Biosynthesis of Mupirocin by Pseudomonas fluorescens NCIMB 10586 Involves Parallel Pathways

A continuous assay for monitoring the synthetic and proofreading activities of multiple aminoacyl-tRNA synthetases for high-throughput drug discovery

Segmental motion in pseudomonic acid A: A carbon-13 spin-lattice relaxation time study at two field strengths.

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