6 research outputs found
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The synthesis and biological evaluation of a library of autoinducer-antibiotic conjugates
Microbial resistance to antibiotics is a serious global health threat, and the discovery of new, safe and effective antibiotics is required urgently. A new class of antibiotics, namely sideophore-antibiotic conjugates, has shown promise in initial studies. Siderophores are used by bacteria for iron uptake, and so attaching antibiotics to them allows the antibiotic to be carried across cell membranes. This study investigated conjugates designed using a similar approach, but using bacterial autoinducers instead of siderophores. Autoinducers are required for coordination of bacterial behaviours and are involved in the control of swarming, virulence factor production and biofilm formation.
The quorum sensing molecules produced by \textit{Pseudomonas aeruginosa} were chosen for investigation as \textit{P. aeruginosa} is a significant human pathogen which displays high resistance to many antibiotics and uses quorum sensing to coordinate its group behaviours.
Ciprofloxacin and trimethoprim were chosen as the antibiotic partners.
Ciprofloxacin is commonly used against \textit{P. aeruginosa} but resistance to it is developing, whereas \textit{P. aeruginosa} is inherently resistant to trimethoprim.
It was hypothesised that the autoinducers would aid retention of the antibiotics in cells, hence increasing or restoring activity.
An initial library was synthesised in two halves which were coupled together using a copper(I)-catalysed azide-alkyne cycloaddition.
The autoinducers were functionalised with azide groups and the antibiotics (specifically ciprofloxacin and trimethoprim) were functionalised with alkynes.
Two cleavable alkynyl ciprofloxacin derivatives were also included.
A second set of compounds, namely homoserine lactone analogue-ciprofloxacin conjugates were then synthesised, building on the one known report of a conjugate of a quorum sensing modulator and an antibiotic.
The most active conjugate found was a cleavable conjugate of homocysteine thiolactone (a homoserine lactone analogue) and ciprofloxacin. This compound showed enhanced antibacterial activity against \textit{P. aeruginosa} compared to ciprofloxacin, and \textit{P. aeruginosa} may develop less resistance towards it.EPSR
Mechanistic insights into a BINOL-derived phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction.
The reaction of tryptamine and (2-oxocyclohexyl)acetic acid can be catalyzed by 3,3'-bis(triphenylsilyl)-1,1'-bi-2-naphthol phosphoric acid to give an asymmetric 尾-carboline. This reaction was first studied by Holloway et al. ( Org. Lett. 2010 , 12 , 4720 - 4723 ), but their mechanistic work did not explain the high stereoselectivity achieved. This study uses density functional theory and hybrid quantum mechanics/molecular mechanics calculations to investigate this reaction and provide a model to explain its outcome. The step leading to diastereo- and enantioselectivity is an asymmetric Pictet-Spengler reaction involving an N-acyliminium ion bound to the catalyst in a bidentate fashion. This interaction occurs via hydrogen bonds between the two terminal oxygen atoms of the catalyst phosphate group and the hydrogen atoms at N and C2 of the substrate indole group. These bonds hold the transition structure rigidly and thus allow the catalyst triphenylsilyl groups to influence the enantioselectivity.We thank Girton College, Cambridge (research fellowship to M.N.G.), the EPSRC (studentship to M.N.G.), and Unilever for support.The is the final published version. It first appeared at http://pubs.acs.org/doi/abs/10.1021/jo5028134
Diversity oriented biosynthesis via accelerated evolution of modular gene clusters.
Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes
The monolayer structure of 1,2-bis(4-pyridyl)ethylene physisorbed on a graphite surface
The crystalline monolayer of 1,2-bis(4-pyridyl)ethylene physisorbed on a graphite surface at 0.44 monolayers coverage has been observed and characterized by synchrotron X-ray diffraction and differential scanning calorimetry. The experimentally determined monolayer structure has p2 symmetry with lattice parameters a?=?17.77?脜, b?=?13.69?脜 and ??=?39.7掳. The unit cell contains two molecules, which are oriented in a plane parallel to the surface. It is proposed that the molecules are arranged such that they are able to form a weak C鈥揌?路路路?N hydrogen bond between pyridine groups. The monolayer melts at 414?K, which is unusually close to the bulk melting point for a sub-monolayer coverage system. This molecule is chiral when adsorbed on the surface, but both isomers appear in the unit cell leading to no overall chirality in the monolayer.<br/