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Antibacterial activity and multi-targeting mechanism of ruthenium polypyridine complexes with anthraquinone groups against Staphylococcus aureus.

Four new ruthenium (II) polypyridine complexes bearing 18β-glycyrtinic acid derivatives, [Ru(bpy)2L](PF6)2 (Ru1), [Ru(dmb)2L](PF6)2 (Ru2), [Ru(dtb)2L](PF6)2 (Ru3) and [Ru(phen)2L](PF6)2 (Ru4) (bpy = 2,2-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine, dtb = 4,4'-di-tert-butyl-2,2'-bipyridine, phen = 1,10- phenanthroline and L is the GA modified new ligand) were designed and synthesized. Their antimicrobial activities against Staphylococcus aureus (S. aureus) were evaluated and all complexes showed obvious inhibitory effect, especially the minimum inhibitory concentration (MIC) value of Ru2 was 3.9 µg·mL-1. Meanwhile, Ru2 was found that could significantly inhibit the formation of biofilms. The membrane-compromising action mode was suggested to be their potential antibactericidal mechanism. In hemolysis experiments, Ru2 hardly showed cytotoxicity to mammalian erythrocytes. Furthermore, the synergism between Ru2 and common antibiotics, such as ampicillin, chloramphenicol, tetracyclinesand and ofloxacin, against S. aureus was also detected using the checkerboard method. Finally, a mouse skin infection model was established to evaluate the antibacterial activity of Ru2 in vivo, and the results showed that Ru2 could effectively promote wound healing in mice infecting with S. aureus. Moreover, the results of histopathological research were consistent with the results of hemolysis test, indicating that the Ru2 complex was almost non-toxic. Thus, it was demonstrated that the polypyridine ruthenium complexes modified with glycyrtinic acid (GA) is a promising strategy for developing interesting antibacterial agents.

Ruthenium-based antibacterial agents with a membrane-disruptive mechanism were designed and synthesized. The complex Ru2 showed excellent antibacterial activity against S. aureus in vitro and in vivo.

The development of new classes of antimicrobial is urgently needed due to the widespread occurrence of multi-resistant pathogens. In this study, three novel ruthenium complexes: [Ru(dmob)2(BTPIP)](PF6)2 (Ru(II)-1), [Ru(dbp)2(BTPIP)](PF6)2 (Ru(II)-2), and [Ru(dpa)2(BTPIP)](PF6)2 (Ru(II)-3) (dpa = 2,2’-dipyridylamine, dmob = 4,4’-dimethoxy-2,2’-bipyridyl, dbp = 4,4’-di- tert-butyl-2,2’-dipyridyl, BTPIP = 4-(benzo[ b]thiophen-2-yl)phenyl-1 H-imidazo[4,5- f][1,10]phenanthroline) are synthesized and investigated as antimicrobial metallodrugs. We demonstrate that all three complexes have significant antimicrobial activity against Staphylococcus aureus by testing their minimal inhibitory concentrations = 0.0015–0.0125 mg/mL. The antibacterial activity of the best active complex Ru(II)-3 is 13 times that of ofloxacin (minimal inhibitory concentration = 19.5 μg/mL). Importantly, Ru(II)-3 not only increases the susceptibility of Staphylococcus aureus to existing common antibiotics but also shows noticeably delayed and decreased resistance in Staphylococcus aureus since the minimal inhibitory concentration values of Ru(II)-3 only increased eightfold times after 20 passages. Furthermore, the biofilms formation and rabbit erythrocyte hemolysis assays verified that Ru(II)-3 also efficiently inhibit the biofilm formation and toxin secretion of Staphylococcus aureus.

Two novel oxovanadium(IV) complexes ([VO(hntdtsc)(BPIP)] and [VO(hntdtsc)(MOPIP)] (hntdtsc = 2-hydroxy-1-naphthaldehydethiosemicarbazone, BPIP = 2-(4-bromophenyl)-imidazo[4,5- f]-1,10-phenanthroline, MOPIP = 2-(4-methoxyphenyl)-imidazo[4,5- f]1,10-phenanthroline), are synthesized and characterized. Subsequently, the Methyl Thiazolyl Tetrazolium (MTT) assay is used to investigate the antitumor activity of the ligand and two complexes in vitro.The results indicate that both complexes could significantly inhibit selected tumor cells (SH-SY5Y, MCF-7, and SK-N-SH). In addition, the antibacterial activity of VO(hntdtsc)(BPIP) against Staphylococcus aureus is further investigated. Interestingly, VO(hntdtsc)(BPIP) can efficiently attenuate S. aureus growth and abrogate α-hemolysin secretion and biofilm formation. The plasmid DNA cleavage activity of both complexes is also investigated. The results suggest that supercoiled plasmid DNA is efficiently cleaved after treatment with each complex, which might contribute to the biological activity of these oxovanadium(IV) complexes.

New effective antimicrobial agents with novel modes of action are urgently needed due to the continued emergence of drug-resistant bacteria. Here, three ruthenium complexes functionalized with benzothiophene: [Ru(phen)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(dmp)2(BTPIP)](ClO4)2 (Ru(II)-2) and [Ru(dmb)2(BTPIP)](ClO4)2 (Ru(II)-3) (dmb = 4,4'-dimethyl-2,2'-bipyridine, phen = 1,10-phenanthroline, dmp = 2,9-dimethyl-1,10-phenanthroline) have been synthesized and their antimicrobial activities in vitro were assessed. Minimum inhibitory concentration (MIC) assays indicated that the three Ru(II)-1, Ru(II)-2 and Ru(II)-3 complexes all showed antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. The most active Ru(II)-3 complex was further tested against biofilms. Furthermore, it was also tested whether complex Ru(II)-3 could serve as an antibacterial adjuvant. Interestingly, the checkerboard data showed that Ru(II)-3 selectively exhibited synergism with aminoglycoside antibiotics. More importantly, the observed synergetic effect might be attributed to the inhibition of the regulatory function of SaCcpA. Finally, in vivo bacterial infection treatment studies through a murine skin infection model and skin irritation test were also conducted. All in all, these results confirmed that ruthenium complexes functionalized with benzothiophene have good antimicrobial activity against Staphylococcus aureus.

There is clearly a need for the development of new classes of antimicrobials to fight against multidrug-resistant bacteria. Here, we designed and synthesized of three ruthenium polypyridyl complexes: [Ru(bpy)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(bpy)2(ETPIP)](ClO4)2 (Ru(II)-2) and [Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-3) (N-N = bpy = 2,2′-bipyridine), their antimicrobial activities against S. aureus were assessed. The lead complexes of this set, Ru(II)-1(MIC = 0.016 mg/mL), was tested against biofilm. We also investigated whether bacteria can easily develop resistance to Ru(II)-1. The result demonstrated that S. aureus could not easily develop resistance to the ruthenium complexes. In addition, aimed to test whether ruthenium complexes treatment could increase the susceptibility of S. aureus to antibiotics, the synergism between Ru(II)-1 and common antibiotics against S. aureus were investigated using the checkerboard method. Interesting, Ru(II)-1 could increased the susceptibility of S. aureus to some aminoglycoside antibiotics(kanamycin and gentamicin). Finally, in vivo bacterial infection treatment studies were also conducted through murine skin infection model. These results confirmed ruthenium complexes have good antimicrobial activity in vitro and in vivo.

Two ruthenium polypyridyl complexes: [Ru(dmb)2(ETPIP)](ClO4)2 (Ru(II)-1) and [Ru(phen)2(ETPIP)](ClO4)2 (Ru(II)-2) (dmb = 4,4′-dimethyl-2,2′-bipyridine, phen = 1,10-phenanthroline, ETPIP = 2-(4-(thiophen-2-ylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), have been synthesized and characterized. Their antimicrobial activities against S. aureus were assessed. Both the complexes Ru(II)-1, and Ru(II)-2 show meaningful activity against Staphylococcus aureus and the lead complex of this set, Ru(II)-2 (MIC = 0.025 mg mL−1), was further tested against biofilms. Given the fact that S. aureus could easily develop resistance to common antimicrobials, we also investigated whether bacteria can easily develop resistance to Ru(II)-2. The result demonstrated that S. aureus did not easily develop resistance to the ruthenium complexes. In addition, the synergism between Ru(II)-2 and common antibiotics against S. aureus was also investigated using the checkerboard method. Interestingly, Ru(II)-2 could increase the susceptibility of S. aureus to the aminoglycoside antibiotic (kanamycin). Finally, a possible mechanism of the observed synergetic effects was investigated by real-time PCR. All in all, these results confirmed that ruthenium complexes have good antimicrobial activity against Staphylococcus aureus.

The development of ruthenium-based complexes or antimicrobial peptides are identified as a promising strategy for combating drug-resistant bacteria. In this work, four biphenyl-based antibacterial ruthenium complexes by targeting membrane integrity, which act as antimicrobial peptides mimics, were designed and synthesized. In vitro antimicrobial screening demonstrated that four complexes could absolutely inhibit the growth of Staphylococcus aureus (S. aureus) with MIC values ranging from 15.6 to 100 μg/mL. The most active complex Ru(Ⅱ)-1 (MIC = 15.6 μg/mL) could kill S. aureus through targeting the membrane integrity without detectably resistance frequencies. Further investigation including bacteria biofilm formation, hemolysin activity and checkerboard assay were performed as well. The results revealed that Ru(Ⅱ)-1 could inhibit the biofilm formation and α-hemolysis secretion in S. aureus at subinhibitory concentration. More interestingly, the combination use of Ru(Ⅱ)-1 and five traditional antibiotics showing synergistic effect. Finally, based on the mouse model of S. aureus skin infection, Ru(Ⅱ)-1 showed important antibacterial efficacy against S. aureus in vivo, and almost non-toxic against mouse tissue. Our study indicates that introducing membrane targeting ligands onto ruthenium complexes may be an underappreciated strategy for developing antibacterial agents.

Four new ruthenium(II) polypyridine complexes bearing 18β-glycyrrhetinic acid derivatives, [Ru(bpy)

Four new ruthenium polypyridyl complexes, [Ru(bpy)

A copper-catalyzed direct C-H chalcogenation of N-aryl-azaindoles with disulfides is described. This transformation was performed using Earth abundant Cu(OAc)2 as a catalyst, benzoic acid as an additive, air as a terminal oxidant, and readily available diaryl and dialkyldisulfides (or diselenide) as chalcogenation reagents. High functional group tolerance and excellent regioselectivity are demonstrated by the efficient preparation of a wide range of ortho-sulfenylation-7-azaindoles.

Leaf epidermal features are useful for elucidating the taxonomy and systematics of oak species. Quercus Group Ilex has a wide distribution mainly in subtropical areas of Eurasia with rich fossil records since the Oligocene, but no comprehensive study has ever been conducted on its diversity of leaf epidermal features. We compared the leaf epidermal features of 37 species of Quercus Group Ilex and Q. suber from Group Cerris using light microscopy (LM) and scanning electron microscopy (SEM). A total of five trichome types (including three glandular and two non-glandular types) and two trichome base types were found. Leaf epidermal features of Group Ilex show typical xeromorphic features. The stomatal complexes are stephanocytic. The leaf trichome types and trichome base types are stable at inter- and intra-species levels. The trichomes, stomatal sizes and density and the ray arm lengths show a wide variation during developing stages within species. The leaf epidermal features show a highly convergent pattern in the genus Quercus based on tree-mapping analysis, except for the multiple epidermal layers on the adaxial surface supports the monophyletic origin of section Heterobalanus. Cluster analysis of leaf epidermal characters infers two morphological subgroups within Group Ilex: (1) the capitate and (2) the branched uniseriate. The trichomes and trichome base types, and their density are useful for species identification, which can improve the accuracy of assigning fossil leaves to their nearest living relatives in Group Ilex.

BackgroundUnderstanding the origin of genetic variation is the key to predict how species will respond to future climate change. The genusQuercusis a species-rich and ecologically diverse woody genus that dominates a wide range of forests and woodland communities of the Northern Hemisphere.Quercusthus offers a unique opportunity to investigate how adaptation to environmental changes has shaped the spatial genetic structure of closely related lineages. Furthermore,Quercusprovides a deep insight into how tree species will respond to future climate change. This study investigated whether closely relatedQuercuslineages have similar spatial genetic structures and moreover, what roles have their geographic distribution, ecological tolerance, and historical environmental changes played in the similar or distinct genetic structures.ResultsDespite their close relationships, the three main oak lineages (QuercussectionsCyclobalanopsis,Ilex, andQuercus) have different spatial genetic patterns and occupy different climatic niches. The lowest level and most homogeneous pattern of genetic diversity was found in sectionCyclobalanopsis, which is restricted to warm and humid climates. The highest genetic diversity and strongest geographic genetic structure were found in sectionIlex, which is due to their long-term isolation and strong local adaptation.The widespread sectionQuercusis distributed across the most heterogeneous range of environments; however, it exhibited moderate haplotype diversity. This is likely due to regional extinction during Quaternary climatic fluctuation in Europe and North America.ConclusionsGenetic variations of sectionsIlexandQuercuswere significantly predicted by geographic and climate variations, while those of sectionCyclobalanopsiswere poorly predictable by geographic or climatic diversity.Apart from the different historical environmental changes experienced by different sections, variation of their ecological or climatic tolerances and physiological traits induced varying responses to similar environment changes, resulting in distinct spatial genetic patterns.

Additional file 2. Distribution of shared haplotypes of section Ilex (a) and section Quercus (b).

The East Asian subtropics mostly occupied by evergreen broad-leaved forests (EBLFs), is one of the global diversity centers for evergreen oaks. Evergreen oaks are keystone canopy trees in EBLFs with important ecosystem function and crucial significance for regional biodiversity conservation. However, the species composition and diversity of Asian evergreen oaks are poorly understood. Here, we test whether the four chloroplast markers atpI-atpH, matK, psbA-trnH, and ycf1, can discriminate the two evergreen oak sections in Asia – Cyclobalanopsis and Ilex. Two hundred and seventy-two individuals representing 57 species were scanned and 17 species from other oaks sections were included for phylogenetic reconstruction. The genetic diversity of the Quercus sections was also compared. Overall, we found that universal chloroplast DNA (cpDNA) barcoding markers could resolve two clades in Quercus, i.e., subgenus Cerris (Old World Clade) and subgenus Quercus (New World Clade). The chloroplast markers distinguished the main sections, with few exceptions. Each cpDNA region showed no barcoding gap and none of them provided good resolution at the species level. The best species resolution (27.78%) was obtained when three or four markers were combined and analyzed using BLAST. The high conservation of the cpDNA and complicated evolutionary patterns, due to incomplete lineage sorting, interspecific hybridization and introgressions may hinder the ability of cpDNA markers to discriminate different species. When comparing diversification pattern across Quercus sections (Cyclobalanopsis, Ilex, Cerris, Quercus, and Protobalanus), we found that section Ilex was the most genetically diverse, and section Cyclobalanopsis was lower genetically diverse. This diversification pattern may have resulted from the interplay of the Eurasia Cenozoic tectonic movements, climate changes and different niches of their ancestral lineages.

Aeschynanthus longicaulisplants are understory plants in the forest, adapting to low light conditions in their native habitats. To observe the effects of the high irradiance on growth and physiology, plants were grown under two different light levels, PPFD 650 μmol·m–2·s–1and 150 μmol·m–2·s–1for 6 months. Plants under high irradiance had significantly thicker leaves with smaller leaf area, length, width, and perimeter compared to the plants grown under low irradiance. Under high irradiance, the leaf color turned yellowish and the total chlorophyll decreased from 5.081 mg·dm−2to 3.367 mg·dm−2. The anthocyanin content of high irradiance leaves was double that of those under low irradiance. The plants under high irradiance had significantly lower Amax(5.69 μmol·m–2·s–1) and LSP (367 μmol·m–2·s–1) and higher LCP (21.9 μmol·m–2·s–1). The chlorophyll fluorescence parameterFv/Fmwas significantly lower and NPQ was significantly higher in high irradiance plants. RLCs showed significantly lowerETRmax⁡andEkin plants under high irradiance. It can be concluded that the maximum PPFD of 650 μmol·m–2·s–1led to significant light stress and photoinhibition ofA. longicaulis.