Antibacterial Design Research Articles

RETRACTED: Embedded medical platform hardware design and application of antibacterial drugs for respiratory infections

The combination of cloud computing and medicine, telemedicine, post-discharge care plan, and such virtual compliance with the drug can improve many medical-related functions. Also, to improve access to healthcare services through telemedicine. The reader to their various application types of the medical field and the processor before this. Description of peripheral equipment and tools to be used in embedded systems are also discussed here. Our focus is the medical equipment of the new era, and we, too, contains some of the existing medical equipment. A variety of bacterial infections is a significant problem for humans and a health threat. Revealing antimicrobial compounds' interactions with a biological agent has stimulated scientists to find new solutions to treat these diseases. (Personal Computer) PC, smartphone, tablet, wearable. Cloud computing technology access storage through a device connected to the Internet and files, software, and on the server to enable the user. Where the cloud computing providers store and process data are separated from the end-user. Antibiotics are rarely as long and not required to treat upper respiratory tract infections that doctors do not suspect a bacterial infection; you should generally avoid. In this way, a simple, such as to cover the surface properly wash their hand's technology, while coughing or sneezing, you can reduce the spread of respiratory infections. It will introduce some basic concepts related to antimicrobial agents. Novel compounds describe the correlation between the activity in vitro and in vivo synthetic path way and antibacterial substances specific design techniques, and polymeric materials. Mechanism of action, and efficacy in vivo, its raw data is reviewed about selecting antimicrobial resistance mechanisms most commonly used.

The hypothetical periplasmic protein PA1624 from Pseudomonas aeruginosa folds into a unique two-domain structure.

The crystal structure of the 268-residue periplasmic protein PA1624 from the opportunistic pathogen Pseudomonas aeruginosa PAO1 was determined to high resolution using the Se-SAD method for initial phasing. The protein was found to be monomeric and the structure consists of two domains, domains 1 and 2, comprising residues 24-184 and 185-268, respectively. The fold of these domains could not be predicted even using state-of-the-art prediction methods, and similarity searches revealed only a very distant homology to known structures, namely to Mog1p/PsbP-like and OmpA-like proteins for the N- and C-terminal domains, respectively. Since PA1624 is only present in an important human pathogen, its unique structure and periplasmic location render it a potential drug target. Consequently, the results presented here may open new avenues for the discovery and design of antibacterial drugs.

A comparative QSAR analysis, 3D-QSAR, molecular docking and molecular design of iminoguanidine-based inhibitors of HemO: A rational approach to antibacterial drug design

QSAR models of 25 iminoguanidine derivatives with inhibitory HemO were developed. The QSAR model was built by using DFT-MLR and the best QSAR model has R2, Q2 values of 0.6569 and 0.5493 for cross-validated and non-cross-validated. The predictive ability of QSAR model was further validated by a test set of 7 compounds, giving R2pred value of 0.7123. 3D-QSAR and docking studies were used to find the actual conformations of chemicals in active site of HemO, as well as the binding mode pattern to the binding site in HemO enzyme. Molecular dynamics and simulations study revealed that A-chain of HemO protein was stable at and above 100ps with respect to temperature (at and above 298 K), electrostatic (at and above 57500 kJ/mol), kinetic energy (at and above 12200 kJ/mol) and total energy (at and above 30500 kJ/mol). The information provided by QSAR, 3D-QSAR and molecular docking may provide a better understanding of the structural requirements of iminoguanidine-based inhibitors of HemO and help to design potential antibacterial molecules. Four (4) new compounds (4A, 5A, 6A, and 7A) with high predicted antibacterial activities have been theoretically designed and they are expected to be confirmed experimentally.

RNA drug discovery: Conformational restriction enhances specific modulation of the T-box riboswitch function

Antibacterial drug resistance is a global health concern that requires multiple solution approaches including development of new antibacterial compounds acting at novel targets. Targeting regulatory RNA is an emerging area of drug discovery. The T-box riboswitch is a regulatory RNA mechanism that controls gene expression in Gram-positive bacteria and is an exceptional, novel target for antibacterial drug design. We report the design, synthesis and activity of a series of conformationally restricted oxazolidinone-triazole compounds targeting the highly conserved antiterminator RNA element of the T-box riboswitch. Computational binding energies correlated with experimentally-derived Kd values indicating the predictive capabilities for docking studies within this series of compounds. The conformationally restricted compounds specifically inhibited T-box riboswitch function and not overall transcription. Complex disruption, computational docking and RNA binding specificity data indicate that inhibition may result from ligand binding to an allosteric site. These results highlight the importance of both ligand affinity and RNA conformational outcome for targeted RNA drug design.

Synthesis, structural, spectral and antibacterial activity of 3,3a,4,5-tetrahydro-2H-benzo[g]indazole fused carbothioamide derivatives as antibacterial agents

The crystal, spectral characteristics and antibacterial activityof two benzo[g]indazole fused carbothioamide derivatives are explained in this study. The structural characterization of our compounds 3-(4-methylphenyl)-N-phenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-2-carbothioamide (BICT) and 3‐(4‐methoxyphenyl)‐N‐(4‐nitrophenyl)‐ 3,3a,4,5-tetrahydro-2H-benzo[g]indazole-2-carbothioamide (MNPBICT) using SCXRD technique is reported. The crystal structures of our derivatives are substantiated with 1H, 13C NMR and FTIR spectral methods. For the synthesized compounds, in silico drug likeness screening using SwissADME online server and DNA gyrase inhibition activity through molecular docking studies (PDB ID: 1KZN) with bacterial protein are reported. The antibacterial activity of our compounds are tested against S. Aureus, B. megaterium, P. Aeroginosa and E. coli bacterial strains by disk broth dilution method. From the in silico pharmacological screening and docking results, it is found that our compound MNPBICT possess higher druggable nature and are effective DNA gyrase inhibitor against protein 1KZN compared to BICT and drug ciprofloxacin. The in vitro analysis explored the promising antibacterial activity of derivative MNPBICT and could be considered as a lead compounds for antibacterial drug design.

Biochemical characterization of ferric uptake regulator (Fur) from Aliivibrio salmonicida. Mapping the DNA sequence specificity through binding studies and structural modelling

Iron is an essential nutrient for bacteria, however its propensity to form toxic hydroxyl radicals at high intracellular concentrations, requires its acquisition to be tightly regulated. Ferric uptake regulator (Fur) is a metal-dependent DNA-binding protein that acts as a transcriptional regulator in maintaining iron metabolism in bacteria and is a highly interesting target in the design of new antibacterial drugs. Fur mutants have been shown to exhibit decreased virulence in infection models. The protein interacts specifically with DNA at binding sites designated as ‘Fur boxes’. In the present study, we have investigated the interaction between Fur from the fish pathogen Aliivibrio salmonicida (AsFur) and its target DNA using a combination of biochemical and in silico methods. A series of target DNA oligomers were designed based on analyses of Fur boxes from other species, and affinities assessed using electrophoretic mobility shift assay. Binding strengths were interpreted in the context of homology models of AsFur to gain molecular-level insight into binding specificity.

Functional and structural analysis of trehalose-6-phosphate phosphatase from Burkholderia pseudomallei: Insights into the catalytic mechanism

We report the functional and structural characterization of trehalose-6-phosphate phosphatase (TPP), from the Gram-negative bacterium B. pseudomallei that causes melioidosis, a severe infectious disease endemic in Southeast Asia and Northern Australia. TPP is a key enzyme in the trehalose biosynthesis pathway, which plays an important role in bacterial stress responses. Due to the absence of this biosynthetic pathway in mammals, TPP has drawn attention as a potential drug target, to combat antibiotic resistance.In this context, we present a detailed biochemical analysis of purified recombinant TPP, reporting its specific high catalytic activity toward the trehalose-6-phosphate substrate, and an absolute requirement for its Mg2+ cofactor. Furthermore, we present the crystal structure of TPP solved at 1.74 Å, revealing the canonical haloacid dehalogenase (HAD) superfamily fold and conserved substrate binding pocket, from which insights into the catalytic mechanism may be deduced. Our data represent a starting point for the rational design of antibacterial drugs.

Interaction of N-3-oxododecanoyl homoserine lactone with transcriptional regulator LasR of Pseudomonas aeruginosa: Insights from molecular docking and dynamics simulations

Background: In 2017, the World Health Organization announced a list of the most dangerous superbugs. Among them is Pseudomonas aeruginosa, an opportunistic human pathogen with high levels of resistance to antibiotics that is listed as one of the ‘ESKAPE’ pathogens, which are the leading cause of nosocomial infections. A major issue is that it mostly affects vulnerable patients such as those suffering from AIDS, cystic fibrosis, cancer and severe burns. P. aeruginosa creates and inhabits surface-associated biofilms which increase resistance to antibiotics and host immune responses and contribute to the ineffectiveness of current antibacterial treatments. It is therefore imperative to find new antibacterial treatment strategies against P. aeruginosa. The LasR protein is a major transcriptional activator of P. aeruginosa and plays a pivotal role in biofilm formation and the activation of many virulence genes, although detailed characteristics of the LasR protein are not currently known. In the present study, we aimed to analyse the molecular properties of the LasR protein as well as its interactions with the signalling molecule N-3-oxododecanoyl homoserine lactone (3OC12-HSL). Methods: We used a combination of molecular docking, molecular dynamics (MD) simulations and machine learning techniques to study the interaction of the LasR protein with the 3OC12-HSL ligand. We assessed conformational changes occurring upon their interaction and analysed the molecular details of their binding. Results: A new possible interaction site for 3OC12-HSL and LasR was found, involving conserved residues from the ligand binding domain (LBD), beta turns in the short linker region (SLR) and the DNA-binding domain (DBD). This interaction is referred to as the LBD-SLR-DBD bridge or ‘the bridge’ interaction. Conclusions: This study may enable future experimental studies to detect the interaction of signalling molecules with “the bridge” of the LasR protein and suggests a potential new interaction site to assist antibacterial drug design.

Anthranilic Acid Inhibitors of Undecaprenyl Pyrophosphate Synthase (UppS), an Essential Enzyme for Bacterial Cell Wall Biosynthesis.

We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from Escherichia coli. UppS is an essential enzyme in the biosynthesis of bacterial cell wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new cis-double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antibacterial drug design. A pharmacophore model was designed on a known bisphosphonate BPH-629 and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three anthranilic acid derivatives with promising inhibitory activity against UppS. Compound 2 displayed high inhibitory potency (IC50 = 25 μM) and good antibacterial activity against E. coli BW25113 ΔtolC strain (MIC = 0.5 μg/mL).

Reaching toward underexplored targets in antibacterial drug design.

The increase of antimicrobial resistance necessitates the renewal and strong research involvement in antibacterial drug design. In the following work, we comment on the key approaches used in development of new antibacterials, focusing on intracellular therapeutic targets that have been so far mostly underexplored: the enzymes of the Mur pathway MurA to MurF. We identify common obstacles observed during research on MurA, MurB, and Mur ligases inhibitors and their development into potential antibacterial compounds, and discern several approaches and solutions to tackle the whole-cell activity of designed compounds. Furthermore, we consolidate recent literature reports and encourage the further research on Mur enzymes.

Prediction of bacteriophage proteins located in the host cell using hybrid features

The identification of bacteriophage proteins in the host subcellular localization could provide important clues for understanding the interaction between phage and host bacteria as well as antibacterial drug design. To date, computational methods have been reported to identify bacteriophage proteins located in the host cell. However, there is still space for improving the prediction accuracy. The existing methods considering the sequence order correlation and the physicochemical property of protein provide us insights to construct an integrated descriptor based on sequence for phage proteins. Meanwhile, we proposed a feature selection technique to obtain the optimal features. In the jackknife test, the prediction accuracies are 86.7% and 97.9%, respectively for discrimination between PH proteins and non-PH proteins as well as PHM proteins and PHC proteins. Based on our model, we updated the web server PHPred to version 2.0 which can be freely accessed from http://lin-group.cn/server/PHPred2.0.

Targeting the Thioredoxin Reductase-Thioredoxin System from Staphylococcus aureus by Silver Ions.

The thioredoxin system, which is composed of NADPH, thioredoxin reductase (TrxR), and thioredoxin (Trx), is one of the major disulfide reductase systems used by bacteria against oxidative stress. In particular, this reductase system is crucial for the survival of the pathogenic bacterium Staphylococcus aureus, which lacks a natural glutathione/glutaredoxin (Grx) system. Although silver ions and silver-containing materials have been used as antibacterial agents for centuries, the antibacterial mechanism of silver is not well-understood. Herein, we demonstrate that silver ions bind to the active sites of S. aureus TrxR and Trx with dissociation constants of 1.4 ± 0.1 μM and 15.0 ± 5.0 μM and stoichiometries of 1 and 2 Ag+ ions per protein, respectively. Importantly, silver ion binding leads to oligomerization and functional disruption of TrxR as well as Trx. Silver also depleted intracellular thiol levels in S. aureus, disrupting bacterial thiol-redox homeostasis. Our study provides new insights into the antibacterial mechanism of silver ions. Moreover, the Trx and TrxR system might serve as a feasible target for the design of antibacterial drugs.

QSAR modeling of dihydrofolate reductase inhibitors as a therapeutic target for multiresistant bacteria

Antibacterial resistance is a growing public health threat of major concern around the world so development of new therapeutic approaches to prevent bacterial multidrug resistance has become a primary consideration for medicinal chemistry research. QSAR models for the dihydrofolate reductase inhibition with 2,4-diamino-5-(substituted-benzyle)-pyramidine derivatives were developed with further computer-aided design of new derivatives with desired activity. The Monte Carlo method has been used as a computational tool for QSAR modeling. For the representation of molecular structure and optimal descriptor calculation, the simplified molecular input line entry system (SMILES) together with the molecular graph (hydrogen-suppressed graph—HSG, hydrogen-filled graph—HFG, and the graph of atomic orbitals-GAO) was used. One-variable models have been calculated for one data split into training, test, and validation set. The impact of Morgan’s extended connectivity index on built QSAR models and outliers was determined. Statistical parameters for the best QSAR model are satisfying. Structural indicators (molecular fragments) responsible for the increase and the decrease of the stated activity are defined, and with the application of defined structural alerts, the computer-aided design of new derivatives with desired activity is presented. Computational experiments presented and applied in this research can satisfactorily predict desired endpoint and can be used further for computer-aided antibacterial drug design.

Two-Component Signal Transduction Systems of Pathogenic Bacteria As Targets for Antimicrobial Therapy: An Overview.

The bacterial communities in a wide range of environmental niches sense and respond to numerous external stimuli for their survival. Primarily, a source they require to follow up this communication is the two-component signal transduction system (TCS), which typically comprises a sensor Histidine kinase for receiving external input signals and a response regulator that conveys a proper change in the bacterial cell physiology. For numerous reasons, TCSs have ascended as convincing targets for antibacterial drug design. Several studies have shown that TCSs are essential for the coordinated expression of virulence factors and, in some cases, for bacterial viability and growth. It has also been reported that the expression of antibiotic resistance determinants may be regulated by some TCSs. In addition, as a mode of signal transduction, phosphorylation of histidine in bacteria differs from normal serine/threonine and tyrosine phosphorylation in higher eukaryotes. Several studies have shown the molecular mechanisms by which TCSs regulate virulence and antibiotic resistance in pathogenic bacteria. In this review, we list some of the characteristics of the bacterial TCSs and their involvement in virulence and antibiotic resistance. Furthermore, this review lists and discusses inhibitors that have been reported to target TCSs in pathogenic bacteria.

Crystal structure determination of a chimeric FabF by XRD

Beta-ketoacyl-acyl-carrier-protein synthase II, an important enzyme in biosynthesis of bacterial fatty acid, is an attractive target in antibacterial drug design. Platensimycin (PTM), produced by Streptomyces platensis, has a strong, broad-spectrum Gram-positive antibacterial activity by selectively targeting to FabF but exhibits no inhibition to the FabF from Streptomyces platensis (spFabF). To study the self-resistance mechanism within the PTM-producing strain and provide hint for development of novel antibiotics, it is imperative to solve the structure of spFabF and elucidate the difference between spFabF and other FabFs which are not resistant to PTM. To this end, we constructed four chimeric FabFs based on the sequence of spFabF and its homologous protein after the expression of wide-type spFabF was failed. The crystal structure of one chimera, js200FabF, of 91.2% sequence identity to spFabF, was solved. A structure comparison of js200FabF with a PTM-bound FabF suggested that three loops nearby the catalytic site might play key roles in preventing the binding of PTM to spFabF. The results provide an encouraging basis for further studies on the self-resistance mechanism and structure-based design of novel antibiotics targeting FabFs.

Anion-selective Formate/nitrite transporters: taxonomic distribution, phylogenetic analysis and subfamily-specific conservation pattern in prokaryotes

BackgroundThe monovalent anions formate, nitrite and hydrosulphide are main metabolites of bacterial respiration during anaerobic mixed-acid fermentation. When accumulated in the cytoplasm, these anions become cytotoxic. Membrane proteins that selectively transport these monovalent anions across the membrane have been identified and they belong to the family of Formate/Nitrite Transporters (FNTs). Individual members that selectively transport formate, nitrite and hydrosulphide have been investigated. Experimentally determined structures of FNTs indicate that they share the same hourglass helical fold with aquaporins and aquaglyceroporins and have two constriction regions, namely, cytoplasmic slit and central constriction. Members of FNTs are found in bacteria, archaea, fungi and protists. However, no FNT homolog has been identified in mammals. With FNTs as potential drug targets for many bacterial diseases, it is important to understand the mechanism of selectivity and transport across these transporters.ResultsWe have systematically searched the sequence databases and identified 2206 FNT sequences from bacteria, archaea and eukaryotes. Although FNT sequences are very diverse, homology modeling followed by structure-based sequence alignment revealed that nearly one third of all the positions within the transmembrane region exhibit high conservation either as a group or at the level of individual residues across all three kingdoms. Phylogenetic analysis of prokaryotic FNT sequences revealed eight different subgroups. Formate, nitrite and hydrosulphide transporters respectively are clustered into two (FocA and FdhC), three (NirC-α, NirC-β and NirC-γ) and one (HSC) subfamilies. We have also recognized two FNT subgroups (YfdC-α and YfdC-β) with unassigned function. Analysis of taxonomic distribution indicates that each subfamily prefers specific taxonomic groups. Structure-based sequence alignment of individual subfamily members revealed that certain positions in the two constriction regions and some residues facing the interior show subfamily-specific conservation. We have also identified examples of FNTs with the two constriction regions formed by residues that are less frequently observed. We have developed dbFNT, a database of FNT models and associated details. dbFNT is freely available to scientific community.ConclusionsTaxonomic distribution and sequence conservation of FNTs exhibit subfamily-specific features. The conservation pattern in the central constriction and cytoplasmic slit in the open and closed states are distinct for YfdC and NirC subfamilies. The same is true for some residues facing the interior of the transporters. The specific residues in these positions can exert influence on the type of solutes that are transported by these proteins. With FNTs found in many disease-causing bacteria, the knowledge gained in this study can be used in the development and design of anti-bacterial drugs.

Insight into the C-F bond mechanism of molecular analogs for antibacterial drug design

The activities of biological molecules usually rely on both of intra-molecular and intermolecular interactions between their function groups. These interactions include interonic attraction theory, Van der Waal’s forces and the function of geometry on the individual molecules, whether they are naturally or synthetic. The purpose of this study was to evaluate the antibacterial activity of C-F bond compound using combination of experiments verification and theoretical calculation. We target on the insect natural products from the maggots of Chrysomyis megacephala Fabricius. Based on density functional theory(DFT) and B3LYP method, a theoretical study of the C-F bond on fluoride was designed to explore compounds 2 and 4 antibacterial structure–activity relationship. With the progress in DFT, first-principle calculation based on DFT has gradually become a routine method for drug design, quantum chemistry and other science fields.

Synergistic antibacterial effect of silver and ebselen against multidrug‐resistant Gram‐negative bacterial infections

Multidrug‐resistant (MDR) Gram‐negative bacteria account for a majority of fatal infections, and development of new antibiotic principles and drugs is therefore of outstanding importance. Here, we report that five most clinically difficult‐to‐treat MDR Gram‐negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells. The silver and ebselen combination causes a rapid depletion of glutathione and inhibition of the thioredoxin system in bacteria. Silver ions were identified as strong inhibitors of Escherichia coli thioredoxin and thioredoxin reductase, which are required for ribonucleotide reductase and DNA synthesis and defense against oxidative stress. The bactericidal efficacy of silver and ebselen was further verified in the treatment of mild and acute MDR E. coli peritonitis in mice. These results demonstrate that thiol‐dependent redox systems in bacteria can be targeted in the design of new antibacterial drugs. The silver and ebselen combination offers a proof of concept in targeting essential bacterial systems and might be developed for novel efficient treatments against MDR Gram‐negative bacterial infections.

TransferRNAmethyltransferaseswithaSpoU-TrmD (SPOUT)foldandtheirmodifiednucleosidesin tRNA.

The existence of SpoU-TrmD (SPOUT) RNA methyltransferase superfamily was first predicted by bioinformatics. SpoU is the previous name of TrmH, which catalyzes the 2’-O-methylation of ribose of G18 in tRNA; TrmD catalyzes the formation of N1-methylguanosine at position 37 in tRNA. Although SpoU (TrmH) and TrmD were originally considered to be unrelated, the bioinformatics study suggested that they might share a common evolution origin and form a single superfamily. The common feature of SPOUT RNA methyltransferases is the formation of a deep trefoil knot in the catalytic domain. In the past decade, the SPOUT RNA methyltransferase superfamily has grown; furthermore, knowledge concerning the functions of their modified nucleosides in tRNA has also increased. Some enzymes are potential targets in the design of anti-bacterial drugs. In humans, defects in some genes may be related to carcinogenesis. In this review, recent findings on the tRNA methyltransferases with a SPOUT fold and their methylated nucleosides in tRNA, including classification of tRNA methyltransferases with a SPOUT fold; knot structures, domain arrangements, subunit structures and reaction mechanisms; tRNA recognition mechanisms, and functions of modified nucleosides synthesized by this superfamily, are summarized. Lastly, the future perspective for studies on tRNA modification enzymes are considered.

SCMBYK: prediction and characterization of bacterial tyrosine-kinases based on propensity scores of dipeptides.

BackgroundBacterial tyrosine-kinases (BY-kinases), which play an important role in numerous cellular processes, are characterized as a separate class of enzymes and share no structural similarity with their eukaryotic counterparts. However, in silico methods for predicting BY-kinases have not been developed yet. Since these enzymes are involved in key regulatory processes, and are promising targets for anti-bacterial drug design, it is desirable to develop a simple and easily interpretable predictor to gain new insights into bacterial tyrosine phosphorylation. This study proposes a novel SCMBYK method for predicting and characterizing BY-kinases.ResultsA dataset consisting of 797 BY-kinases and 783 non-BY-kinases was established to design the SCMBYK predictor, which achieved training and test accuracies of 97.55 and 96.73%, respectively. Furthermore, the leave-one-phylum-out method was used to predict specific bacterial phyla hosts of target sequences, gaining 97.39% average test accuracy. After analyzing SCMBYK-derived propensity scores, four characteristics of BY-kinases were determined: 1) BY-kinases tend to be composed of α-helices; 2) the amino-acid content of extracellular regions of BY-kinases is expected to be dominated by residues such as Val, Ile, Phe and Tyr; 3) BY-kinases structurally resemble nuclear proteins; 4) different domains play different roles in triggering BY-kinase activity.ConclusionsThe SCMBYK predictor is an effective method for identification of possible BY-kinases. Furthermore, it can be used as a part of a novel drug repurposing method, which recognizes putative BY-kinases and matches them to approved drugs. Among other results, our analysis revealed that azathioprine could suppress the virulence of M. tuberculosis, and thus be considered as a potential antibiotic for tuberculosis treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1371-4) contains supplementary material, which is available to authorized users.