The action mechanism of daptomycin

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.bmc.2016.05.052 © 2016.Daptomycin is a lipopeptide antibiotic produced by the soil bacterium Streptomyces roseosporus that is clinically used to treat severe infections with Gram-positive bacteria. In this review, we discuss the mode of action of this important antibiotic. Although daptomycin is structurally related to amphomycin and similar lipopeptides that inhibit peptidoglycan biosynthesis, experimental studies have not produced clear evidence that daptomycin shares their action mechanism. Instead, the best characterized effect of daptomycin is the permeabilization and depolarization of the bacterial cell membrane. This activity, which can account for daptomycin's bactericidal effect, correlates with the level of phosphatidylglycerol (PG) in the membrane. Accordingly, reduced synthesis of PG or its increased conversion to lysyl-PG promotes bacterial resistance to daptomycin. While other resistance mechanisms suggest that daptomycin may indeed directly interfere with cell wall synthesis or cell division, such effects still await direct experimental confirmation. Daptomycin's complex structure and biosynthesis have hampered the analysis of its structure activity relationships. Novel methods of total synthesis, including a recent one that is carried out entirely on a solid phase, will enable a more thorough and systematic exploration of the sequence space

An Acyl-Linked Dimer of Daptomycin Is Strongly Inhibited by the Bacterial Cell Wall

This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publi-cation in ACS Infectious Diseases,© American Chemical Society after peer review. To access the final edited and published work see http://pubs.acs.org/doi/full/10.1021/acsinfecdis.7b00019.The lipopeptide antibiotic daptomycin is active against Gram-positive pathogens. It permeabilizes bacterial cell membranes, which involves the formation of membrane-associated oligomers. We here studied a dimer of daptomycin whose two subunits were linked through a bivalent aliphatic acyl chain. Unexpectedly, the dimer had very low activity on vegetative Staphylococcus aureus and Bacillus subtilis cells. However, activity resembled that of monomeric daptomycin on liposomes and on B. subtilis L-forms. These findings underscore the importance of the bacterial cell wall in daptomycin resistance.NSERC operating grants to M.P. (250265-2013) and S.T. (155283-2012)

Probing the Gamma-Ray Burst Rate with Trigger Simulations of the Swift Burst Alert Telescope

The long gamma-ray burst (GRB) rate is essential for revealing the connection between GRBs, supernovae and stellar evolution. Additionally, the GRB rate at high redshift provides a strong probe of star formation history in the early universe. While hundreds of GRBs are observed by Swift, it remains difficult to determine the intrinsic GRB rate due to the complex trigger algorithm of Swift. Current studies usually approximate the Swift trigger algorithm by a single detection threshold. However, unlike the previously flown GRB instruments, Swift has over 500 trigger criteria based on photon count rate and additional image threshold for localization. To investigate possible systematic biases and explore the intrinsic GRB properties, we developed a program that is capable of simulating all the rate trigger criteria and mimicking the image trigger threshold. We use this program to search for the intrinsic GRB rate. Our simulations show that adopting the complex trigger algorithm of Swift increases the detection rate of dim bursts. As a result, we find that either the GRB rate is much higher than previously expected at large redshift, or the luminosity evolution is non-negligible. We will discuss the best results of the GRB rate in our search, and their impact on the star-formation history.Comment: 6 pages, 3 figures, 7th Huntsville Gamma-Ray Burst Symposium, GRB 2013: paper 35 in eConf Proceedings C130414

Probing the Cosmic Gamma-Ray Burst Rate with Trigger Simulations of the Swift Burst Alert Telescope

The gamma-ray burst (GRB) rate is essential for revealing the connection between GRBs, supernovae and stellar evolution. Additionally, the GRB rate at high redshift provides a strong probe of star formation history in the early universe. While hundreds of GRBs are observed by Swift, it remains difficult to determine the intrinsic GRB rate due to the complex trigger algorithm of Swift. Current studies of the GRB rate usually approximate the Swift trigger algorithm by a single detection threshold. However, unlike the previously flown GRB instruments, Swift has over 500 trigger criteria based on photon count rate and additional image threshold for localization. To investigate possible systematic biases and explore the intrinsic GRB properties, we develop a program that is capable of simulating all the rate trigger criteria and mimicking the image threshold. Our simulations show that adopting the complex trigger algorithm of Swift increases the detection rate of dim bursts. As a result, our simulations suggest bursts need to be dimmer than previously expected to avoid over-producing the number of detections and to match with Swift observations. Moreover, our results indicate that these dim bursts are more likely to be high redshift events than low-luminosity GRBs. This would imply an even higher cosmic GRB rate at large redshifts than previous expectations based on star-formation rate measurements, unless other factors, such as the luminosity evolution, are taken into account. The GRB rate from our best result gives a total number of 4571^{+829}_{-1584} GRBs per year that are beamed toward us in the whole universe. SPECIAL NOTE (2015.05.16): This new version incorporates an erratum. All the GRB rate normalizations ($R_{\rm GRB}(z=0)$) should be a factor of 2 smaller than previously reported. Please refer to the Appendix for more details. We sincerely apologize for the mistake.Comment: 52 pages, 17 figures, published in ApJ 783, 24L (2014). An erratum is included. A typo in Eq. 8 is fixed in this versio

Membrane binding and oligomer formation by the calcium-dependent lipopeptide antibiotic A54145: a quantitative study with pyrene excimer fluorescence

The final publication is available at Elsevier via http://doi.org/10.1016/j.bpj.2016.07.018 © 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/A54145 is a lipopeptide antibiotic related to daptomycin that permeabilizes bacterial cell membranes. Its action requires both calcium and phosphatidylglycerol in the target membrane, and it is accompanied by the formation of membrane-associated oligomers. We here probed the interaction of A54145 with model membranes composed of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol, using the steady-state and time-resolved fluorescence of a pyrene-labeled derivative (Py-A54145). In solution, the labeled peptide was found to exist as a monomer. Its membrane interaction occurred in two stages that could be clearly distinguished by varying the calcium concentration. In the first stage, which was observed between 0.15 and 1 mM calcium, Py-A54145 bound to the membrane, as indicated by a strong increase in pyrene monomer emission. At the same calcium concentration, excimer emission increased also, suggesting that Py-A54145 had oligomerized. A global analysis of the time-resolved pyrene monomer and excimer fluorescence confirmed that Py-A54145 forms oligomers quantitatively and concomitantly with membrane binding. When calcium was raised beyond 1 mM, a distinct second transition was observed that may correspond to a doubling of the number of oligomer subunits. The collective findings confirm and extend our understanding of the action mode of A54145 and daptomycin.This work was supported by the Natural Sciences and Engineering Research Council of Canada operating grants to J.D. (201603-2013), M.P. (250265-2013), and S.T. (155283-2012)

Cognitive improvement following repair of a basal encephalocele.

We report the case of a 55-year-old woman presenting with progressive memory impairment secondary to a transsphenoidal encephalocele involving her dominant medial temporal lobe. Her clinical deterioration was accompanied by radiological progression in the encephalocele's size and associated encephalomalacia. Through a temporal craniotomy, her encephalocele was resected and the defect closed. Baseline neuropsychological assessment indicated global cognitive impairment, but post-operatively, she reported improved memory and concentration. Standardized assessment reflected an improvement in perceptual skills and an associated improved recall of a complex figure. This is the first case report to date of a patient's memory improving following treatment of a basal encephalocele

Characterization of daptomycin oligomerization with perylene excimer fluorescence: Stoichiometric binding of phosphatidylglycerol triggers oligomer formation

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.bbamem.2011.10.027 © 2012. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Daptomycin is a lipopeptide antibiotic that binds to and depolarizes bacterial cell membranes. Its antibacterial activity requires calcium and correlates with the content of phosphatidylglycerol in the target membrane. Daptomycin has been shown to form oligomers on liposome membranes. We here use perylene excimer fluorescence to further characterize the membrane-associated oligomer. To this end, the N-terminal fatty acyl chain was replaced with perylene-butanoic acid. The perylene derivative retains one third of the antibacterial activity of native daptomycin. On liposomes containing phosphatidylcholine and phosphatidylglycerol, as well as on Bacillus subtilis cells, the perylene-labeled daptomycin forms excimers, which shows that the N-terminal acyl chains of neighboring oligomer subunits are in immediate contact with one another. In a lipid bicelle system, oligomer formation can be titrated with stoichiometric amounts of phosphatidylglycerol. Therefore, the interaction of daptomycin with a single molecule of phosphatidylglycerol is sufficient to trigger daptomycin oligomerization.NSERC operating grants to M. Palmer and S. D. Taylor. || J. Muraih was supported by a scholarship from the government of Ira

Export Tourism: Input-Output Multipliers in Ireland - A reply. Quarterly Economic Commentary Special Article, November 1983

In the course of an article on "Export Tourism Input-Output Multipliers for Ireland" in the ESRI Quarterly Economic Commentary of May 1982 Desmond A. G. Norton derived some estimates in respect of tourism activity and drew comparisons between his estimates and those of others including Byrne and Palmer. The following comments are set out in order to indicate sources of these differences

Chapter 2: Dumbart jen jen – first steps

This chapter is written as a conversation (held in December 2016) between David Palmer (host), Ingrid Cumming, Jennie Buchanan (both Research Associates of the project) and Gideon Digby (President of Wikimedia Australia), who introduce themselves and go on to discuss their roles in the Noongarpedia adventure