D-Ala-D-lac binding is not required for the high activity of vancomycin dimers against vancomycin resistant enterococci

Covalent dimerization and oligomerization of vancomycin is an important and extensively used strategy to develop analogues active against vancomycin resistant enteroccoci (VRE). Here, we have carried out investigations to probe the role of peptide binding (Lys-d-Ala-d-Lac) in the high anti-VRE activities of covalently linked vancomycin dimers. Covalent dimers of damaged vancomycin (desleucyl) were prepared, and their anti-VRE activities and binding affinities toward various model peptides were measured. Despite the dramatic loss in affinity toward several model peptides in comparison to the corresponding intact vancomycin dimers, these damaged dimers maintained good activity against VRE. These results strongly suggest that the high anti-VRE activities of covalent vancomycin dimers are conferred from mechanisms other than Lys-d-Ala-d-Lac binding.     

Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorial synthesis

Based on the notion that dimerization and/or variation of amino acid 1 of vancomycin could potentially enhance biological activity, a series of synthetic and chemical biology studies were undertaken in order to discover potent antibacterial agents. Herein we describe two ligation methods (disulfide formation and olefin metathesis) for dimerizing vancomycin derivatives and applications of target-accelerated combinatorial synthesis (e.g. combinatorial synthesis in the presence of vancomycin's target Ac2-L-Lys-D-Ala-D-Ala) to generate libraries of vancomycin dimers. Screening of these compound libraries led to the identification of a number of highly potent antibiotics effective against vancomycin-suspectible, vancomycin-intermediate resistant and, most significantly, vancomycin-resistant bacteria.     

Solid- and solution-phase synthesis of vancomycin and vancomycin analogues with activity against vancomycin-resistant bacteria

Vancomycin, the prototypical member of the glycopeptide family of antibiotics, is a clinically used antibiotic employed against a variety of drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The recent emergence of vancomycin resistance, viewed as a growing threat to public health, prompted us to initiate a program aimed at restoring the potency of this important antibiotic through chemical manipulation of the vancomycin structure. Herein, we describe the development of synthetic technology based on the design of a novel selenium safety catch linker, application of this technology to a solid-phase semisynthesis of vancomycin, and the solid- and solution-phase synthesis of vancomycin libraries. Biological evaluation of these compound libraries led to the identification of a number of in vitro highly potent antibacterial agents effective against vancomycin-resistant bacteria. In addition to aiding these investigations, the solid-phase chemistry described herein is expected to enhance the power of combinatorial chemistry and facilitate chemical biology and medicinal chemistry studies.     

Multivalent drug design. Synthesis and in vitro analysis of an array of vancomycin dimers

The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dimers are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity against susceptible and drug-resistant Gram-positive pathogens. To prepare the array, monomeric vancomycin synthons were linked through four distinct positions of the glycopeptide (C-terminus (C), N-terminus (N), vancosamine residue (V), and resorcinol ring (R)) in 10 unique pairwise combinations. Amphiphilic, peptide-based linkers of four different lengths (11, 19, 27, and 43 total atoms) were employed. Both linkage orientation and linker length were found to affect in vitro antibacterial potency. The V-V series displayed the greatest potency against vancomycin-susceptible organisms and vancomycin-resistant Enterococcus faecalis (VRE) of VanB phenotype, while the C-C, C-V, and V-R series displayed the most promising broad-spectrum activity that included VRE of VanA phenotype. Dimers bearing the shortest linkers were in all cases preferred for activity against VRE. The effects of linkage orientation and linker length on in vitro potency were not uniform; for example, (1) no single compound displayed activity that was superior against all test organisms to that of vancomycin or the other dimers, (2) linker length effects varied with test organism, and (3) whereas one-half of the dimers were more potent than vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA), only one dimer was more potent against methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate susceptible S. aureus (GISA). In interpreting the results, we have considered the potential roles of multivalency and of other phenomena.     

Novel abietane diterpenoids and aromatic compounds from Cladonia rangiferina and their antimicrobial activity against antibiotics resistant bacteria

From Cladonia rangiferina were isolated two novel abietane diterpenoids, hanagokenols A (1) and B (2). Also in this investigation, four known abitetane diterpenoids (3-6), four known labdane diterpenoids (7-10), one known isopimarane diterpenoid (11), and six known aromatic compounds were isolated. These structures were elucidated primarily through extensive NMR experiments. Hanagokenol A (1) was a unique abietane diterpene having an ether linkage between C-6 and C-18 of sugiol. Hanagokenol B (2) is also a unique secoabietane diterpene, having gamma-lactone which occurred by cleavage and subsequently oxidation between C-6/C-7 of 12-hydroxydehydroabietinol. Furthermore, all the isolated compounds (1-17) were tested for the antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE).     

Multifunctional divalent vancomycin: the fluorescent imaging and photodynamic antimicrobial properties for drug resistant bacteria

A simple and specific divalent vancomycin-porphyrin has been developed. This divalent vancomycin-porphyrin conjugate indicates promising properties in fluorescent imaging and photodynamic inactivation of vancomycin-sensitive and vancomycin-resistant enterococci (VRE) bacterial strains.     

Synthesis, characterization, and antimicrobial activity of silver carbene complexes derived from 4,5,6,7-tetrachlorobenzimidazole against antibiotic resistant bacteria

Silver N-heterocyclic carbene complexes have been shown to have great potential as antimicrobial agents, affecting a wide spectrum of both Gram-positive and Gram-negative bacteria. A new series of three silver carbene complexes (SCCs) based on 4,5,6,7-tetrachlorobenzimidazole has been synthesized, characterized, and tested against a panel of clinical strains of bacteria. The imidazolium salts and their precursors were characterized by elemental analysis, mass spectrometry, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction. The silver carbene complexes, SCC32, SCC33, and SCC34 were characterized by elemental analysis, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction. These complexes proved highly efficacious with minimum inhibitory concentrations (MICs) ranging from 0.25 to 6 μg mL(-1). Overall, the complexes were effective against highly resistant bacteria strains, such as methicillin-resistant Staphylococcus aureus (MRSA), weaponizable bacteria, such as Yersinia pestis, and pathogens found within the lungs of cystic fibrosis patients, such as Pseudomonas aeruginosa, Alcaligenes xylosoxidans, and Burkholderia gladioli. SCC33 and SCC34 also showed clinically relevant activity against a silver-resistant strain of Escherichia coli based on MIC testing.     

Synthesis of Gossypium hirsutum‐derived silver nanoparticles and their antibacterial efficacy against plant pathogens

Malvaceae and Brassicaceae family crops are economically important; however, their production has been markedly decreased in recent years due to various plant pests. Hence, the search for novel classes of efficient biological approaches continues due to unavailability of precise pesticides. The present study was designed to synthesize, characterize and evaluate the efficacy of silver nanoparticles (AgNPs) obtained using stem extract of Gossypium hirsutum (cotton plant) against plant pathogens Xanthomonas axonopodis pv. malvacearum and Xanthomonas campestris pv. campestris. Biosynthesized AgNPs were characterized using UV–visible spectrophotometry, Dynamic Light Scattering, Scanning Electron Microscopy combined with energy‐dispersive X‐ray analysis and Fourier transform infrared spectroscopy. The synthesized AgNPs were spherical in shape with size ranging from 20 to 100 nm. The characterized AgNPs were investigated for their efficacy against bacterial plant pathogens using the paper disc method. In vitro studies with two concentrations of AgNPs (50 and 100 μg mL^?1) showed zone of inhibition 11.0 ± 1.0 and 12.3 ± 0.5 mm for X. axonopodis pv. malvacearum and 9.7 ± 0.6 and 15.33 ± 1.0 mm for X. campestris pv. campestris. Furthermore, the AgNPs exhibited strong antioxidant activity, and a phytotoxicity study on Vigna unguiculata (cowpea plant) showed no toxicity. Overall, the findings suggest that G. hirsutum stem extract could be efficiently used in the synthesis of AgNPs and showed antimicrobial activity against plant pathogens. Hence, the synthesized nanoparticles could be used to combat plant pathogens in the agriculture sector.     

Anthracene carboxyimides and their dimers

Soluble anthracenedicarboxyimides have been prepared and undergo a photodimerisation of the anthracene skeleton, which is important for their application as antitumour agents, such as azonafides. Reaction under strongly alkaline conditions causes C-C coupling to form soluble dimeric fluorescent dyes with bathochromic absorption and fluorescence in the NIR region. These dyes are of special interest because of their absorption at longer wavelengths.     

Artemisinin-derived dimers and their antimalarial activities

Malaria is a tropical disease that leads around half a million people to succumb annually. Antimalarial agents such as artemisinin and its derivatives are crucial to malaria treatment; however, the rapid development of drug resistance to clinically used antimalarials is still the major obstacle to effective chemotherapy. To tackle the growing resistance issue, new antimalarial agents are urgently needed. Using artemisinin-derived dimers as pharmacological scaffolds has demonstrated promising antimalarial activity; therefore, rational design of the dimers may provide valuable therapeutic intervention to treat malaria or even drug-resistant malaria. This review emphasized two aspects: (a) different linker-tethered artemisinin-derived dimers with potential antimalarial activity and (b) the structure-activity relationships discussed to provide an insight for rational design of dimers with improved efficiency.     

Synthesis of defined ubiquitin dimers

Many proteins are post-translationally modified by the attachment of poly-ubiquitin (Ub) chains. Notably, the biological function of the attached Ub chain depends on the specific lysine residue used for conjugate formation. Here, we report an easy and efficient method to synthesize site-specifically linked Ub dimers by click reaction between two artificial amino acids. In fact, we were able to synthesize all seven naturally occurring Ub connectivities, providing the first example of a method that gives access to all Ub dimers. Furthermore, these synthetic Ub dimers are recognized by the natural ubiquitination machinery and are proteolytically stable, making them optimal candidates to further investigate the function of differently linked Ub chains.     

Chip-calorimetric evaluation of the efficacy of antibiotics and bacteriophages against bacteria on a minute-timescale

Rapid detection of antibiotic resistances of clinical bacterial strains would allow an early selective antibiotic therapy and a faster intervention and implementation of infection control measurements. In clinical practice, however, conventional antibiotic susceptibility tests of bacteria often need 24 h until the results are obtained. The metabolic heat production of bacteria is an excellent possibility to record their physiological activities and could therefore be used for a rapid discrimination of bacterial strains which are resistant or non-resistant to antibiotics and also to lytic bacteriophages, respectively. Unfortunately, conventional calorimeters suffer from need of comparably large volumes of bacterial suspensions are characterised by slow operation and high costs which restrict their application in clinical laboratories. The present paper demonstrates that a new type of calorimeters developed on silicon-chip technology enables the detection of antibiotic resistances on a minute-timescale. For this reasons, a prototype chip calorimeter was used which sensitivity is 20 nW related to the heat production of about 10⁴ bacteria. For a clear discrimination of antibiotic resistance about 10⁵ bacteria are required. The antibiotic resistances and susceptibilities of different strains of Staphylococcus aureus to cefoxitin and the sensitivities of S. aureus DSM 18421 and E. coli DSM 498 to a mixture of two bacteriophages were studied. Comparing the heat productions of cultures incubated with antibiotics or bacteriophages to those without these antibacterial preparations enabled a clear discrimination of resistant and non-resistant strains already after totally 2 h.     

Synthesis and copolymerization behavior of methacrylate dimers

Methacrylic ester-based dimers and oligomers were synthesized using a metal-based catalytic chain transfer agent. Conditions were employed which maximized the yield of unsaturated dimers, and the copolymerization behavior of these dimers was investigated. The molecular weight and polymer yield were found to decrease with increasing dimer concentration in the copolymerization feeds. © 1993 John Wiley & Sons, Inc.     

Synthesis and self-inclusion of bipyridine-spaced cyclodextrin dimers

The synthesis and conformational behavior of two cyclodextrin dimers containing aromatic bipyridine spacers is presented. The proton NMR spectra of these dimers in aqueous solution show a doubling of signals in the aromatic region due to complete or partial self-inclusion of the spacer. The degree and the strength of self-inclusion is dependent on the substitution pattern of the bipyridine unit. This unexpected difference in the self-inclusion behavior is revealed by 2D NOESY and circular dichroism spectra.     

Synthesis and properties of aralkylamine C-nitroso dimers

The action of 3-chloroperbenzoic acid on eleven aralkylamines yielded the C-nitroso dimers; physical properties of the compounds, including UV, IR, NMR and MS data are reported. The stability of the nitroso dimers was investigated. The 2-nitroso-1-phenylpropane dimer was converted into its hydrazo-, azo- and azoxy-derivatives.     

Synthesis of chloroquinocin, a pyranonaphthoquinone antibiotic against Gram-positive bacteria

Chloroquinocin 1 is an antimicrobial agent against Gram-positive bacteria, including MRSA (methicillin-resistant Staphylococcus aureus). A successful synthesis of 1 was attained through a unique chlorination of the corresponding naphthoquinone derivative 12 as a key step.     

Phytogenic-mediated silver nanoparticles using Persicaria hydropiper extracts and its catalytic activity against multidrug resistant bacteria

Multidrug resistance (MDR) is one of the major global threats of this century. So new innovative approaches are needed for the development of existing antibiotics to limit antibacterial resistance. The current study was aimed to utilize extracts of root, stem, and leaves of Persicaria hydropiper for the synthesis of silver nanoparticles (AgNPs) using standard procedure. Synthesis of AgNPs was evident from the change in color of the solution to dark brownish and then it was further revealed by UV–Vis and Fourier Transformed Infrared Spectroscopy (FTIR). UV–Vis spectroscopy has revealed absorbance peak at 370 nm while, FTIR spectrum displayed that aromatics amines were used as reducing agent in the fabrication of AgNPs. In addition, Scanning Electron Microscopy (SEM micrograph) displaying tetrahedron, spherical and oval shapes of synthesized AgNPs whereas, average size of synthesized AgNPs was found in the range of 32–77 nm. Beside this, it was also observed that the potency of antibiotics against MDR bacteria increased after coating with synthesized AgNPs i.e., the potency of Ceftazidime and Ciprofloxacin increased up to 450% and 500% against Bacillus respectively while, the potency of Gentamicin, Vancomycin and Linezolid increased up to 150%, 200% and 58% against Bacillus, Staphylococcus, and Proteus species respectively. Furthermore, it was concluded that utilizing AgNPs in combination with commercially available antibiotics would provide an alternate therapy for the treatment of infectious diseases caused by MDR bacteria.     

A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria

The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from d-Ala-d-Ala to d-Ala-d-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Ψ[C(═NH)NH]Tpg(4)]vancomycin aglycon designed to exhibit the dual binding to d-Ala-d-Ala and d-Ala-d-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model d-Ala-d-Ala ligand was found to be only 2-fold less than vancomycin aglycon and this affinity was maintained with a model d-Ala-d-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibits potent antimicrobial activity against vancomycin-resistant bacteria (MIC = 0.31 μg/mL, VanA VRE). Thus, a complementary single atom exchange in the vancomycin core structure (O → NH) to counter the single atom exchange in the cell wall precursors of resistant bacteria (NH → O) reinstates potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections.