Novel Small-Molecule Hybrid-Antibacterial Agents against S. aureus and MRSA Strains

Ongoing resistance developments against antibiotics that also affect last-resort antibiotics require novel antibacterial compounds. Strategies to discover such novel structures have been dimerization or hybridization of known antibacterial agents. We found novel antibacterial agents by dimerization of indols and hybridization with carbazoles. They were obtained in a simple one-pot reaction as bisindole tetrahydrocarbazoles. Further oxidation led to bisindole carbazoles with varied substitutions of both the indole and the carbazole scaffold. Both the tetrahydrocarbazoles and the carbazoles have been evaluated in various S. aureus strains, including MRSA strains. Those 5-cyano substituted derivatives showed best activities as determined by MIC values. The tetrahydrocarbazoles partly exceed the activity of the carbazole compounds and thus the activity of the used standard antibiotics. Thus, promising lead compounds could be identified for further studies.     

Twisted amides inferred from QSAR analysis of hydrophobicity and electronic effects on the affinity of fluoroaromatic inhibitors of carbonic anhydrase.

QSAR has been used to elucidate the origin of the hydrophobicity and binding affinity of a small library of fluoroaromatic inhibitors of F131V carbonic anhydrase II. Our analysis predicted the presence of a twisted amide conformation for several bound inhibitors, which we confirmed crystallographically. We also determined that the hydrophobicity of the inhibitors as a whole results from the fragment hydrophobicities of their fluorobenzyl rings, corrected for field effects and the presence of an intramolecular F.H contact in solution. The loss of this interaction on binding to the enzyme makes the affinity sensitive to the same terms, but with the opposite dependence on the F.H contact. In the case of the four inhibitors bound as twisted amides, this F.H contact must be retained to some extent in the bound state in order for their affinities to be consistent with our QSAR analysis of the entire set of 17 molecules.     

3D QSAR analyses of novel tyrosine kinase inhibitors based on pharmacophore alignment

In an effort to develop a quantitative ligand-binding model for the receptor tyrosine kinases, a pharmacophore search was first used to identify structural features that are common in two novel sets of 12 molecules of the 3-substituted indolin-2-ones and 19 compounds of the benzylidene malononitriles with low-to-high affinity for HER2, a kind of receptor tyrosine kinase. The common pharmacophore model based on these 31 compounds was used as a template to obtain the aligned molecular aggregate, which provided a good starting point for 3D-QSAR analysis of only the 19 benzylidene malononitriles. Two molecular field analysis (MFA) techniques, including CoMFA and CoMSIA, were used to derive the quantitative structure-activity relationships of the studied molecules. From the studied results, it was obvious that the 3D-QSAR models based on the pharmacophore alignment were superior to those based on the simple atom-by-atom fits. Considering the flexibility of the studied molecules and the difference between the active conformers and the energy-lowest conformers, the pharmacophore model can usually provide the common features for the flexible regions. Moreover, the best CoMSIA model based on the pharmacophore hypothesis gave good statistical measure from partial least-squares analysis (PLS) (q(2) = 0.71), which was slightly better than the CoMFA one. Our study demonstrated that pharmacophore modeling and CoMSIA research could be effectively combined. Results obtained from both methods helped with understanding the specific activity of some compounds and designing new specific HER2 inhibitors.     

A 3D QSAR pharmacophore model and quantum chemical structure--activity analysis of chloroquine(CQ)-resistance reversal

Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.     

两种细菌的毛细管电泳分离及其与药物相互作用的研究

通过对大肠杆菌与金黄色葡萄球菌的毛细管电泳行为的研究,包括对细菌样品预处理、缓冲液、检测波长以及聚合物添加剂对分离度的改进等的考察,在优化的实验条件下,实现了大肠杆菌与金黄色葡萄球菌的快速分离,从而建立一种新的细菌辅助识别与定性的补充方法。将抗菌药物阿奇霉素与金黄色葡萄球菌混合培育,发现由于阿奇霉素抑制细菌表面蛋白合成,造成与金黄色葡萄球菌作用后,细菌表面电荷密度降低,表现为阿奇霉素对金黄色葡萄球菌的电泳淌度的影响,而且培育时间与金黄色葡萄球菌的淌度线性相关。     

Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(iii) complex of a ciprofloxacin-functionalized linear desferrichrome, Galbofloxacin, with a cleavable serine linker as a potent therapeutic for S. aureus bacterial infections. We employed characterization using in vitro inhibitory assays, radiochemical, tracer-based uptake and pharmacokinetic assessment of our lead compound, culminating in in vivo efficacy studies in a soft tissue model of infection. Galbofloxacin exhibits a minimum inhibitory concentration of (MIC₉₈) 93 nM in wt S. aureus, exceeding the potency of the parent antibiotic ciprofloxacin (0.9 μM). Galbofloxacin is a protease substrate that can release the antibiotic payload in the bacterial cytoplasm. Radiochemical experiments with wt bacterial strains reveal that ⁶⁷Galbofloxacin is taken up efficiently using siderophore mediated, active uptake. Biodistribution of ⁶⁷Galbofloxacin in a mouse model of intramuscular S. aureus infection revealed renal clearance and enhanced uptake in infected muscle when compared to ⁶⁷Ga-citrate, which showed no selectivity. A subsequent in vivo drug therapy study reveals efficient reduction in S. aureus infection burden and sustained survival with Galbofloxacin for 7 days. Ciprofloxacin had no treatment efficacy at identical molecular dose (9.3 μmol kg⁻¹) and resulted in death of all study animals in <24 hours. Taken together, the favorable bacterial growth inhibitory, pharmacokinetic and in vivo efficacy properties qualify Galbofloxacin as the first rationally designed Ga-coordination complex for the management of S. aureus bacterial infections.

Galbofloxacin, a novel theranostic xenosiderophore antibiotic, exhibits unparalleled potency in combating S. aureus infections in vivo.     

Philip S. Magee: a life in QSAR

A brief account of the career of Philip S. Magee, a distinguished member of the QSAR community.     

A three-dimensional chemical phase pharmacophore mapping,QSAR modelling and electronic feature analysis of benzofuran salicylic acid derivatives as LYP inhibitors

Lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has a critical negative regulatory role in T-cell antigen receptor (TCR) and emerged as a promising drug target for human autoimmune diseases. A five-point pharmacophore with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic ring features was generated for a series of benzofuran salicylic acid derivatives as LYP inhibitors in order to elucidate their anti-autoimmune activity. The generated pharmacophore yielded a significant 3D-QSAR model with r² of 0.9146 for a training set of 27 compounds. The model also showed excellent predictive power with Q² of 0.7068 for a test set of eight compounds. The investigation of the 3D-QSAR model has revealed the structural insights which could lead to more potent analogues. The most active and inactive compounds were further subjected to electronic structure analysis using density functional theory (DFT) at B3LYP/3?21^?G level to support the 3D-QSAR predictions. The results obtained from this study are expected to be useful in the proficient design and development of benzofuran salicylic acid derivatives as inhibitors of LYP.     

Electrochemical study on the natural and chemical preservatives antibacterial effect against S. aureus PTCC 1112 and its determination at low levels

Journal of the Iranian Chemical Society - Pathogen microorganisms detection, such as Staphylococcus aureus (S. aureus), is so critical because it can be dangerous for public health. In this...     

U.S. EPA Regulatory Perspectives on the Use of QSAR for New and Existing Chemical Evaluations

Abstract

As testing is not required, ecotoxicity or fate data are available for ≈ 5% of the approximately 2,300 new chemicals/year (26,000 + total) submitted to the US-EPA. The EPA's Office of Pollution Prevention and Toxics (OPPT) regulatory program was forced to develop and rely upon QSARs to estimate the ecotoxicity and fate of most of the new chemicals evaluated for hazard and risk assessment. QSAR methods routinely result in ecotoxicity estimations of acute and chronic toxicity to fish, aquatic invertebrates, and algae, and in fate estimations of physical/chemical properties, degradation, and bioconcentration. The EPA's Toxic Substances Control Act (TSCA) Inventory of existing chemicals currently lists over 72,000 chemicals. Most existing chemicals also appear to have little or no ecotoxicity or fate data available and the OPPT new chemical QSAR methods now provide predictions and cross-checks of test data for the regulation of existing chemicals. Examples include the Toxics Release Inventory (TRI), the Design for the Environment (DfE), and the OECD/SIDS/HPV Programs. QSAR screening of the TSCA Inventory has prioritized thousands of existing chemicals for possible regulatory testing of: 1) persistent bioaccumulative chemicals, and 2) the high ecotoxicity of specific discrete organic chemicals.     

Combining 4D pharmacophore generation and multidimensional QSAR: modeling ligand binding to the bradykinin B2 receptor

We recently reported the development of two receptor-modeling concepts (software Quasar and Raptor) based on multidimensional quantitative structure-activity relationships (QSAR) and allowing for the explicit simulation of induced fit. As the identification of the bioactive configuration of ligand molecules in such studies is all but unambiguous, each compound may be represented by an ensemble of different conformations, orientations, stereoisomers, and protonation states, leading to a 4D data set. In this account, we present a novel technology (software Symposar) allowed to automatically generate a 4D pharmacophore as input for multidimensional QSAR. Symposar aligns ligands utilizing fuzzylike 2D-subfeature mapping and, subsequently, a Monte Carlo search on a 3D similarity grid. The two-step concept (4D pharmacophore generation and quantification of ligand binding by multidimensional QSAR) was applied to 186 compounds binding to the bradykinin B2 receptor. The prediction of their binding affinity by means of the Quasar and Raptor technologies allowed for consensus scoring and generated topologically and quantitatively consistent receptor models. These converged at a cross-validated r2 of 0.752 and 0.815 and yielded a predictive r2 of 0.784 and 0.853 for a test set (for Quasar and Raptor, respectively).     

Toward the pathway of S. aureus WTA biosynthesis

Wall teichoic acid (WTA) contributes profoundly to the virulence of Staphylococcus aureus. The successful in vitro reconstitution of poly-ribitolphosphate WTA biosynthesis using recombinant enzymes sheds new light on WTA enzymology and paves the way for developing new antibiotics that target WTA biosynthesis, as discussed in Brown et al. in a recent issue of Chemistry & Biology.     

Three-dimensional quantitative structure-activity relationship (3D QSAR) and pharmacophore elucidation of tetrahydropyran derivatives as serotonin and norepinephrine transporter inhibitors

Three-dimensional quantitative structure-activity relationship (3D QSAR) using comparative molecular field analysis (CoMFA) was performed on a series of substituted tetrahydropyran (THP) derivatives possessing serotonin (SERT) and norepinephrine (NET) transporter inhibitory activities. The study aimed to rationalize the potency of these inhibitors for SERT and NET as well as the observed selectivity differences for NET over SERT. The dataset consisted of 29 molecules, of which 23 molecules were used as the training set for deriving CoMFA models for SERT and NET uptake inhibitory activities. Superimpositions were performed using atom-based fitting and 3-point pharmacophore-based alignment. Two charge calculation methods, Gasteiger-Hückel and semiempirical PM3, were tried. Both alignment methods were analyzed in terms of their predictive abilities and produced comparable results with high internal and external predictivities. The models obtained using the 3-point pharmacophore-based alignment outperformed the models with atom-based fitting in terms of relevant statistics and interpretability of the generated contour maps. Steric fields dominated electrostatic fields in terms of contribution. The selectivity analysis (NET over SERT), though yielded models with good internal predictivity, showed very poor external test set predictions. The analysis was repeated with 24 molecules after systematically excluding so-called outliers (5 out of 29) from the model derivation process. The resulting CoMFA model using the atom-based fitting exhibited good statistics and was able to explain most of the selectivity (NET over SERT)-discriminating factors. The presence of −OH substituent on the THP ring was found to be one of the most important factors governing the NET selectivity over SERT. Thus, a 4-point NET-selective pharmacophore, after introducing this newly found H-bond donor/acceptor feature in addition to the initial 3-point pharmacophore, was proposed.     

Significance analysis and multiple pharmacophore models for differentiating P-glycoprotein substrates

P-glycoprotein (Pgp) mediated drug efflux affects the absorption, distribution, and clearance of a broad structural variety of drugs. Early assessment of the potential of compounds to interact with Pgp can aid in the selection and optimization of drug candidates. To differentiate nonsubstrates from substrates of Pgp, a robust predictive pharmacophore model was targeted in a supervised analysis of three-dimensional (3D) pharmacophores from 163 published compounds. A comprehensive set of pharmacophores has been generated from conformers of whole molecules of both substrates and nonsubstrates of P-glycoprotein. Four-point 3D pharmacophores were employed to increase the amount of shape information and resolution, including the ability to distinguish chirality. A novel algorithm of the pharmacophore-specific t-statistic was applied to the actual structure-activity data and 400 sets of artificial data (sampled by decorrelating the structure and Pgp efflux activity). The optimal size of the significant pharmacophore set was determined through this analysis. A simple classification tree using nine distinct pharmacophores was constructed to distinguish nonsubstrates from substrates of Pgp. An overall accuracy of 87.7% was achieved for the training set and 87.6% for the external independent test set. Furthermore, each of nine pharmacophores can be independently utilized as an accurate marker for potential Pgp substrates.     

Insights into the key structural features of triazolothienopyrimidines as anti-HIV agents using QSAR,molecular docking,and pharmacophore modeling

Structural Chemistry - The development of severe drug resistance caused by the extensive use of anti-HIV agents has resulted in resistance mutation that compromise efficacy of anti-retroviral. We...     

PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results

We introduce PHASE, a highly flexible system for common pharmacophore identification and assessment, 3D QSAR model development, and 3D database creation and searching. The primary workflows and tasks supported by PHASE are described, and details of the underlying scientific methodologies are provided. Using results from previously published investigations, PHASE is compared directly to other ligand-based software for its ability to identify target pharmacophores, rationalize structure-activity data, and predict activities of external compounds.     

QSAR modeling of toxicities of ionic liquids toward Staphylococcus aureus using SMILES and graph invariants

Structural Chemistry - Ionic liquids (ILs) have been popular in many industrial and chemical processes, like antimicrobial properties, solvents, and synthesis of new compounds with antioxidant...