Antibacterial Target Research Articles

An in silico approach for identification of lead compound as FtsZ inhibitor.

The remarkable conservation of the FtsZ among Gram-positive and Gram-negative bacteria, a crucial GTPase in bacterial cell division, has emerged as a promising antibacterial drug target to combat antibacterial resistance. There have been several coordinated efforts to develop inhibitors against FtsZ which can also serve as potential candidates for future antibiotics. In the present study, a natural product-like library (≈50,000 compounds) was employed to conduct HTVS against Staphylococcus aureus FtsZ protein (PDB Id: 6KVP). Additionally, molecular docking was carried out in two modes, SP and XP docking, using the Schrödinger suite. The glide scores of ligands obtained by XP docking were further summarized and compared with the control ligands (ZI1- co-crystal and PC190723-a compound undergoing clinical trial). Using the Prime-MM-GBSA approach, BFE calculations were performed on the top XP-scored ligands (≈598 compounds). These hits were also evaluated for ADMET parameters using the Qikprop algorithm, SwissADME, and in silico carcinogenicity testing using Carcinopred-El. Based on the results, ligand 4-FtsZ complex was considered for the 300ns MDS analysis to get insights into its binding modes within the catalytic pocket of FtsZ protein. The analysis revealed that the amide linkage sandwiched between the triazole and 1-oxa-8-azaspirodecan-8-ium moiety (Val203) as well as the aminoethyl group present at 1st position on the triazole moiety (Leu209, Leu200, Asp210, and Ala202) were responsible for the FtsZ inhibitory activity, owing to their crucial interactions with key amino acid residues. Further, the complex also displayed good protein-ligand stability, ultimately predicting ligand 4 as a potent lead compound for the inhibition of FtsZ. Thus, our in silico findings will serve as a framework for in-depth in-vitro and in-vivo investigations encouraging the development of FtsZ inhibitors as a new generation of antibacterial agents.

Development of Penicillin-Based Carbonic Anhydrase Inhibitors Targeting Multidrug-Resistant Neisseria gonorrhoeae.

The development of antibacterial drugs with new mechanisms of action is crucial in combating the rise of antibiotic-resistant infections. Bacterial carbonic anhydrases (CAs, EC 4.2.1.1) have been validated as promising antibacterial targets against pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, and vancomycin-resistant enterococci. A multitarget strategy is proposed to design penicillin-based CA inhibitor hybrids for tackling resistance by targeting multiple bacterial pathways, thereby resensitizing drug-resistant strains to clinical antibiotics. The sulfonamide derivatives potently inhibited the CAs from N. gonorrhoeae and Escherichia coli with KI values in the range of 7.1-617.2 nM. Computational simulations with the main penicillin-binding protein (PBP) of N. gonorrhoeae indicated that these hybrid derivatives maintained the mechanism of action of the lead β-lactams. A subset of derivatives showed potent PBP-related antigonococcal effects against multidrug-resistant N. gonorrhoeae strains, with several compounds significantly outperforming both the lead β-lactam and CA inhibitor drugs (MIC values in the range 0.25 to 0.5 μg/mL).

Signal Propagation in the ATPase Domain of Mycobacterium tuberculosis DNA Gyrase from Dynamical-Nonequilibrium Molecular Dynamics Simulations.

DNA gyrases catalyze negative supercoiling of DNA, are essential for bacterial DNA replication, transcription, and recombination, and are important antibacterial targets in multiple pathogens, including Mycobacterium tuberculosis, which in 2021 caused >1.5 million deaths worldwide. DNA gyrase is a tetrameric (A2B2) protein formed from two subunit types: gyrase A (GyrA) carries the breakage-reunion active site, whereas gyrase B (GyrB) catalyzes ATP hydrolysis required for energy transduction and DNA translocation. The GyrB ATPase domains dimerize in the presence of ATP to trap the translocated DNA (T-DNA) segment as a first step in strand passage, for which hydrolysis of one of the two ATPs and release of the resulting inorganic phosphate is rate-limiting. Here, dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations of the dimeric 43 kDa N-terminal fragment of M. tuberculosis GyrB show how events at the ATPase site (dissociation/hydrolysis of bound nucleotides) are propagated through communication pathways to other functionally important regions of the GyrB ATPase domain. Specifically, our simulations identify two distinct pathways that respectively connect the GyrB ATPase site to the corynebacteria-specific C-loop, thought to interact with GyrA prior to DNA capture, and to the C-terminus of the GyrB transduction domain, which in turn contacts the C-terminal GyrB topoisomerase-primase (TOPRIM) domain responsible for interactions with GyrA and the centrally bound G-segment DNA. The connection between the ATPase site and the C-loop of dimeric GyrB is consistent with the unusual properties of M. tuberculosis DNA gyrase relative to those from other bacterial species.

Isatin based 1,2,3-triazole derivatives as antimicrobial agents: Synthesis, in silico docking and molecular dynamics simulations

With the aim to identify new antimicrobials, in the present study a new series of isatin based 1,2,3-triazoles (5a-5f & 6a-6f) has been synthesized through CuAAC click reaction and characterized by FTIR, NMR and MS spectral methods. In vitro antimicrobial assay suggested that synthesized derivatives exhibited good to high efficacy against tested microorganisms. Compounds 5c, 5d, 5f exhibited promising potency towards E. coli, similarly, 5b, 5d, 5e and 6d displayed good antifungal efficacy against C. albicans. These compounds also exhibited better potency against both the fungal strains as compared to the standard drug. Molecular docking studies of these derivatives performed against antibacterial and antifungal targets 1KZN (E. coli) and 5TZ1(C. albicans) revealed that hybrid 5b possessed lowest binding energy i.e. -9.1 kcal/mol and -11.0 kcal/mol, respectively. Moreover, Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) analysis was used to compute the various components contributing to binding free energy of 5b with these biological targets.

Integrated computational modeling and in-silico validation of flavonoids-Alliuocide G and Alliuocide A as therapeutic agents for their multi-target potential: Combination of molecular docking, MM-GBSA, ADMET and DFT analysis

Alliuocide class of compounds belong to flavonoids and were isolated from Allium cepa. Alliuocide are the key phytoconstituents of Allium cepa having biological activities like anticancer, antidiabetic, anti-allergic, metabolic, and inflammatory disorders, antibacterial as well as effective antioxidants against chronic diseases. However, after their isolation report, there was no further work done and a gap of about 10 years. Herein, the present study was carried out to cover the gap and to identify new lead candidates in drug discovery pipeline. Alliuocide A and G were screened against various antioxidant, antidiabetic, anticancer and antibacterial target proteins. Target based screening by molecular docking against different target receptor co-crystal structure revealed Alliuocide A as potential hit, these results were further demonstrated by MM-GBSA studies. Further optimization of both compounds was done by in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies. Both compounds followed Lipinski's rule of five therefore safe for further in vivo studies. Finally spectral studies along with quantum descriptors were carried out by employing DFT method at 6–311 G (d,p) basis set. These quantum chemical parameters proved to be important mechanism for correlating the inhibition efficiency with molecular quatum parameters. All these studies help in designing of derivatives for better pharmacological potential.

Nanomaterials in Antibacterial Photodynamic Therapy and Antibacterial Sonodynamic Therapy

AbstractAntibacterial photodynamic therapy (aPDT) and antibacterial sonodynamic therapy (aSDT) utilize sensitizers (photosensitizers/sonosensitizers) to produce reactive oxygen species (ROS) for antibacterial treatment under the stimulation of light/ultrasound, which have the characteristics of broad‐spectrum antibacterial properties, low drug‐resistance, and effective targeting of infected tissues. Nanomaterials in aPDT/aSDT are primarily used as nano‐sensitizers or nano‐carriers of sensitizers. They enhance the stability and permeability of sensitizers, improve targeting of sensitizers, strengthen photodynamic/sonodynamic properties of sensitizers (modification of sensitizers absorption efficiency and light/ultrasonic response stress by modulation of nanoparticle shape, size, and structure). Also, they improve modifiability of sensitizers (controlling the release rate and time of the sensitizer as needed to optimize the therapeutic effect), enhance programmability and multifunctionality of sensitizers (flexible application of nanotechnology for designing sensitizers with multiple functions, such as drug delivery, targeted therapy, and therapeutic monitoring), and expand possibilities for combination therapies (the nano‐carriers can be loaded with other therapeutic agents, enabling combination therapies). Nanomaterials are expected to further promote the development of aPDT/aSDT and achieve improved antibacterial effects. This review summarizes the progress in nanomaterials in aPDT/aSDT in recent years and based on the current development strategies to provide a theoretical reference for the application of nanomaterials in aPDT/aSDT.

Photosensitive AIEgens sensitize bacteria to oxidative damage and modulate the inflammatory responses of macrophages to salvage the photodynamic therapy against MRSA

The urgent need for antimicrobial agents to combat infections caused by multidrug-resistant bacteria facilitates the exploration of alternative strategies such as photosensitizer (PS)-mediated photoinactivation. However, increasing studies have discovered uncorrelated bactericidal activities among PSs possessing similar photodynamic and pathogen-targeted properties. To optimize the photodynamic therapy (PDT) against infections, we investigated three type-I PSs of D-π-A AIEgens TI, TBI, and TTI. The capacities of reactive oxygen species (ROS) generation of TI, TBI, and TTI did not align with their bactericidal activities. Despite exhibiting the lowest photodynamic efficiency, TI exhibited the highest activities against methicillin-resistant Staphylococcus aureus (MRSA) by impairing the anti-oxidative responses of bacteria. By comparison, TTI, characterized by the strongest ROS production, inactivated intracellular MRSA by potentiating the inflammatory response of macrophages. Unlike TI and TTI, TBI, despite possessing moderate photodynamic activities and inducing ROS accumulation in both MRSA and macrophages, did not exhibit any antibacterial activity. Therefore, relying on the disturbed anti-oxidative metabolism of pathogens or potentiated host immune responses, transient ROS bursts can effectively control bacterial infections. Our study reevaluates the contribution of photodynamic activities of PSs to bacterial elimination and provides new insights into discovering novel antibacterial targets and agents.

Gyrase and Topoisomerase IV: Recycling Old Targets for New Antibacterials to Combat Fluoroquinolone Resistance.

Beyond their requisite functions in many critical DNA processes, the bacterial type II topoisomerases, gyrase and topoisomerase IV, are the targets of fluoroquinolone antibacterials. These drugs act by stabilizing gyrase/topoisomerase IV-generated DNA strand breaks and by robbing the cell of the catalytic activities of these essential enzymes. Since their clinical approval in the mid-1980s, fluoroquinolones have been used to treat a broad spectrum of infectious diseases and are listed among the five "highest priority" critically important antimicrobial classes by the World Health Organization. Unfortunately, the widespread use of fluoroquinolones has been accompanied by a rise in target-mediated resistance caused by specific mutations in gyrase and topoisomerase IV, which has curtailed the medical efficacy of this drug class. As a result, efforts are underway to identify novel antibacterials that target the bacterial type II topoisomerases. Several new classes of gyrase/topoisomerase IV-targeted antibacterials have emerged, including novel bacterial topoisomerase inhibitors, Mycobacterium tuberculosis gyrase inhibitors, triazaacenaphthylenes, spiropyrimidinetriones, and thiophenes. Phase III clinical trials that utilized two members of these classes, gepotidacin (triazaacenaphthylene) and zoliflodacin (spiropyrimidinetrione), have been completed with positive outcomes, underscoring the potential of these compounds to become the first new classes of antibacterials introduced into the clinic in decades. Because gyrase and topoisomerase IV are validated targets for established and emerging antibacterials, this review will describe the catalytic mechanism and cellular activities of the bacterial type II topoisomerases, their interactions with fluoroquinolones, the mechanism of target-mediated fluoroquinolone resistance, and the actions of novel antibacterials against wild-type and fluoroquinolone-resistant gyrase and topoisomerase IV.

Antibiotic's target site affects the potentiation of Lactiplantibacillus plantarum inhibition and inactivation by electroporation.

Antibiotic resistance represents a growing global threat, and thus the motivation to develop novel and combined methods of bacterial inactivation is increasing. Electroporation is a technique in which electric pulses of sufficient strength are applied to permeabilize cells, including bacteria. Combining antibacterials with electroporation is a promising strategy to potentiate their bactericidal and bacteriostatic effectiveness. This approach has already proved useful for increasing bacterial inactivation, yet most studies so far have mainly focused on the maximal achievable effects, and less on the underlying mechanisms. We recently demonstrated that in the Gram-negative (G-) bacterium Escherichia coli, electroporation potentiates antibacterials targeting the peptidoglycan wall more than those with intracellular targets. However, in Gram-positive (G+) bacteria, the wall is directly accessible from the outside, and thus the dependence of potentiation on the antibacterial's target may be rather different. Here, we compare the inactivation and growth inhibition of the G+ bacterium Lactiplantibacillus plantarum for two antibiotics with different modes of action: ampicillin (inhibits cell-wall synthesis) and tetracycline (inhibits intracellular protein synthesis). We used antibiotic concentrations ranging from 0 to 30 × MIC (minimum inhibitory concentration that we predetermined for each antibiotic), a single 1-ms electric pulse with an amplitude from 0 to 20 kV/cm, and post-pulse pre-dilution incubation of 24 h or 1 h. Electroporation increased the inhibition and inactivation efficiency of both antibiotics, but this was more pronounced for tetracycline, with statistical significance mostly limited to 24-h incubation. In general, both inhibition and inactivation grew stronger with increasing antibiotic concentration and electric field amplitude. Our results indicate that electroporation potentiates inactivation of G+ bacteria to a larger extent for antibiotics that inhibit intracellular processes and require transport into the cytoplasm, and to a smaller extent for antibiotics that inhibit cell-wall synthesis. This is the inverse of the relation observed in G- bacteria, and can be explained by the difference in the envelope structure: in G- bacteria the outer membrane must be breached for wall-inhibiting antibiotics to access their target, whereas in G+ bacteria the wall is inherently accessible from the outside and permeabilization does not affect this access.

Treating Pythiosis with Antibacterial Drugs Targeting Protein Synthesis: An Overview.

This review article explores the effectiveness of antibacterial drugs that inhibit protein synthesis in treating pythiosis, a difficult-to-treat infection caused by Pythium insidiosum. The article highlights the susceptibility of P. insidiosum to antibacterial drugs, such as macrolides, oxazolidinones, and tetracyclines. We examine various studies, including in vitro tests, experimental infection models, and clinical case reports. Based on our synthesis of these findings, we highlight the potential of these drugs in managing pythiosis, primarily when combined with surgical interventions. The review emphasizes the need for personalized treatment strategies and further research to establish standardized testing protocols and optimize therapeutic approaches.

Novel 9H‐flouren containing indoline scaffolds: Synthesis, characterization, antimicrobial assays, and molecular docking study

Abstract9H fluoren containing indoline scaffolds were developed by coupling indoline amine with α‐carboxylic acid group of amino acids in the presence of the peptide coupling reagent hexafluorophosphate benzotriazole tetramethyluronium (HBTU). All eight (12a–12h) synthesized indoline scaffolds were analyzed for their potent antibacterial and antifungal activities. The antibacterial assay revealed that compounds 12a, 12b, and 12e have shown excellent activity against pathogenic strains Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes with minimum inhibitory concentration (MIC) values as low as between 25 and 125 μg/mL. The antifungal activity of all synthesized indoline scaffolds were moderate compared with used standard drugs. The molecular docking study of 12a, 12b, and 12e with various antibacterial target proteins from different bacterial strains revealed outstanding interactions which ultimately support antibacterial results.

Inhibition of multiple staphylococcal growth states by a small molecule that disrupts membrane fluidity and voltage.

New molecular approaches to disrupting bacterial infections are needed. The bacterial cell membrane is an essential structure with diverse potential lipid and protein targets for antimicrobials. While rapid lysis of the bacterial cell membrane kills bacteria, lytic compounds are generally toxic to whole animals. In contrast, compounds that subtly damage the bacterial cell membrane could disable a microbe, facilitating pathogen clearance by the immune system with limited compound toxicity. A previously described small molecule, D66, terminates Salmonella enterica serotype Typhimurium (S. Typhimurium) infection of macrophages and reduces tissue colonization in mice. The compound dissipates bacterial inner membrane voltage without rapid cell lysis under broth conditions that permeabilize the outer membrane or disable efflux pumps. In standard media, the cell envelope protects Gram-negative bacteria from D66. We evaluated the activity of D66 in Gram-positive bacteria because their distinct envelope structure, specifically the absence of an outer membrane, could facilitate mechanism of action studies. We observed that D66 inhibited Gram-positive bacterial cell growth, rapidly increased Staphylococcus aureus membrane fluidity, and disrupted membrane voltage while barrier function remained intact. The compound also prevented planktonic staphylococcus from forming biofilms and a disturbed three-dimensional structure in 1-day-old biofilms. D66 furthermore reduced the survival of staphylococcal persister cells and of intracellular S. aureus. These data indicate that staphylococcal cells in multiple growth states germane to infection are susceptible to changes in lipid packing and membrane conductivity. Thus, agents that subtly damage bacterial cell membranes could have utility in preventing or treating disease.IMPORTANCEAn underutilized potential antibacterial target is the cell membrane, which supports or associates with approximately half of bacterial proteins and has a phospholipid makeup distinct from mammalian cell membranes. Previously, an experimental small molecule, D66, was shown to subtly damage Gram-negative bacterial cell membranes and to disrupt infection of mammalian cells. Here, we show that D66 increases the fluidity of Gram-positive bacterial cell membranes, dissipates membrane voltage, and inhibits the human pathogen Staphylococcus aureus in several infection-relevant growth states. Thus, compounds that cause membrane damage without lysing cells could be useful for mitigating infections caused by S. aureus.

Oxacyanopyridine-Benzofuran Hybrids: Synthesis, in silico Toxicity Assessment, in vitro Antimicrobial Activity and Dual Target Docking Studies

This study emphasizes the synthesis and characterization of a novel series of oxa cyano pyridine heterocyclic molecular hybrids (OCP 1-6), integrating pyridine and benzofuran motifs. Meticulously designed from 5-chlorosalicylaldehyde in a multistep process, the synthesized compounds were structurally confirmed through IR spectroscopy, 1H NMR spectroscopy, and mass spectrometry. Computational predictions highlighted diverse properties, including antitubercular and antibacterial attributes, bioactivity scores, toxicity profiles and potential molecular targets. In vitro assessments and Schrödinger docking simulations revealed binding affinities to enzymes viz. Mycobacterium tuberculosis enoyl-ACP reductase and Escherichia coli Topoisomerase IV. Compounds, particularly OCP 2, 3, 4 and 5, exhibited significant antitubercular and antibacterial activities in both in vitro assessments and docking simulations. This study underscores the substantial potential of the synthesized hybrids as promising candidates for further lead optimization, positioning them as valuable contributors to the development of pharmaceutical agents with heightened potency and enhanced safety profiles.

Disruption of an Active Site Network Leads to Activation of C2α-Lactylthiamin Diphosphate on the Antibacterial Target 1-Deoxy-d-xylulose-5-phosphate Synthase.

The bacterial metabolic enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) catalyzes the thiamin diphosphate (ThDP)-dependent formation of DXP from pyruvate and d-glyceraldehyde-3-phosphate (d-GAP). DXP is an essential bacteria-specific metabolite that feeds into the biosynthesis of isoprenoids, pyridoxal phosphate (PLP), and ThDP. DXPS catalyzes the activation of pyruvate to give the C2α-lactylThDP (LThDP) adduct that is long-lived on DXPS in a closed state in the absence of the cosubstrate. Binding of d-GAP shifts the DXPS-LThDP complex to an open state which coincides with LThDP decarboxylation. This gated mechanism distinguishes DXPS in ThDP enzymology. How LThDP persists on DXPS in the absence of cosubstrate, while other pyruvate decarboxylases readily activate LThDP for decarboxylation, is a long-standing question in the field. We propose that an active site network functions to prevent LThDP activation on DXPS until the cosubstrate binds. Binding of d-GAP coincides with a conformational shift and disrupts the network causing changes in the active site that promote LThDP activation. Here, we show that the substitution of putative network residues, as well as nearby residues believed to contribute to network charge distribution, predictably affects LThDP reactivity. Substitutions predicted to disrupt the network have the effect to activate LThDP for decarboxylation, resulting in CO2 and acetate production. In contrast, a substitution predicted to strengthen the network fails to activate LThDP and has the effect to shift DXPS toward the closed state. Network-disrupting substitutions near the carboxylate of LThDP also have a pronounced effect to shift DXPS to an open state. These results offer initial insights to explain the long-lived LThDP intermediate and its activation through disruption of an active site network, which is unique to DXPS. These findings have important implications for DXPS function in bacteria and its development as an antibacterial target.

A hierarchical approach towards identification of novel inhibitors against L, D-transpeptidase YcbB as an anti-bacterial therapeutic target

The bacterial cell wall, being a vital component for cell viability, is regarded as a promising drug target. The L, D-Transpeptidase YcbB enzyme has been implicated for a significant role in cell wall polymers cross linking during typhoid toxin release, β-lactam resistance and outer membrane defect rescue. These observations have been recorded in different bacterial pathogens such as Salmonella Typhimurium, Citrobacter rodentium, and Salmonella typhi. In this work, we have shown structure based virtual screening of diverse natural and synthetic drug libraries against the enzyme and revealed three compounds as LAS_32135590, LAS_34036730 and LAS-51380924. These compounds showed highly stable energies and the findings are very competitive with the control molecule ((1RG or (4 R,5S)-3-({(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl}sulfanyl)-5-[(1S,2R)-1-formyl-2-hydroxypropyl]-4-methyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid or ertapenem)) used. Compared to control (which has binding energy score of −11.63 kcal/mol), the compounds showed better binding energy. The binding energy score of LAS_32135590, LAS_34036730 and LAS-51380924 is −12.63 kcal/mol, −12.22 kcal/mol and −12.10 kcal/mol, respectively. Further, the docked snapshot of the lead compounds and control were investigated for stability under time dependent dynamics environment. All the three leads complex and control system showed significant equilibrium (mean RMSD < 3 Å) both in term of intermolecular docked conformation and binding interactions network. Further validation on the complex’s stability was acquired from the end-state MMPB/GBSA analysis that observed greater contribution from van der Waals forces and electrostatic energy while less contribution was noticed from solvation part. The compounds were also showed good drug-likeness and are non-toxic and non-mutagenic. In short, the compounds can be used in experimental testing’s and might be subjected to structure modification to get better results. Communicated by Ramaswamy H. Sarma

A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens.

The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative species has been limited due in part to poor intracellular accumulation. To address this limitation, we have designed a FtsZ inhibitor (RUP4) that incorporates a chlorocatechol siderophore functionality that can chelate ferric iron (Fe3+) and utilizes endogenous siderophore uptake pathways to facilitate entry into Gram-negative pathogens. We show that RUP4 is active against both Klebsiella pneumoniae and Acinetobacter baumannii, with this activity being dependent on direct Fe3+ chelation and enhanced under Fe3+-limiting conditions. Genetic deletion studies in K. pneumoniae reveal that RUP4 gains entry through the FepA and CirA outer membrane transporters and the FhuBC inner membrane transporter. We also show that RUP4 exhibits bactericidal synergy against K. pneumoniae when combined with select antibiotics, with the strongest synergy observed with PBP2-targeting β-lactams or MreB inhibitors. In the aggregate, our studies indicate that incorporation of Fe3+-chelating moieties into FtsZ inhibitors is an appealing design strategy for enhancing activity against Gram-negative pathogens of global clinical significance.

Synthesis, characterization, optical properties, biological activity and theoretical studies of a 4 nitrobenzylidene) amino) phenyl)imino)methyl)naphthalen-2-ol -based fluorescent Schiff base

A new Schiff base, 1-(E)-(4-((E) 4nitrobenzylidene) amino) phenyl)imino) methyl)naphthalen-2-ol (4NMN), was prepared from the reaction of p-phenylenediamine with 2-hydroxy-1-naphthaldehyde and 4-nitrobenzaldehyde and characterized with spectroscopic analysis. UV-VIS and NMR. Frontier molecular orbitals, molecular electrostatic potential, and chemical reactivity descriptors of the synthesized compound were studied using molecular modeling methods. The antibacterial and antifungal activities of the Schiff base were studied for its minimum inhibitory concentration. The compound showed a higher effect on yeast than against bacteria. Density functional theory (DFT) calculations were performed to study the mechanism of reaction for the synthesis of 4NMN, and the results were consistent with the experimental findings. 4NMN exhibited moderate antibacterial and antifungal activities and demonstrated higher inhibition potential against different resistant strains compared to the reference drug gentamycin. The absorption and fluorescence spectra of 4NMN were measured in different solvents, and the effect of relative polarity and acidity on the medium was observed. An inner filter effect was observed at high concentrations, and the compound showed considerable fluorescence enhancement with increasing medium viscosity and fluorescence quenching by the addition of traces of Cr1+ and Cu2+. Additionally, molecular docking studies were conducted to investigate the efficiency of antibacterial and antifungal targets.

Thiazolotriazoles As Anti-infectives: Design, Synthesis, Biological Evaluation and In Silico Studies.

The rational design of novel thiazolo[2,3-c][1,2,4]triazole derivatives was carried out based on previously identified antitubercular hit molecule H127 for discovering potent compounds showing antimicrobial activity. The designed compounds were screened for their binding efficacies against the antibacterial drug target enoyl-[acyl-carrier-protein] reductase, followed by prediction of drug-likeness and ADME properties. The designed analogues were chemically synthesized, characterized by spectroscopic techniques, followed by evaluation of antimicrobial activity against bacterial and fungal strains, as well as antitubercular activity against M. tuberculosis and M. bovis strains. Among the synthesized compounds, five compounds, 10, 11, 35, 37 and 38, revealed antimicrobial activity, albeit with differential potency against various microbial strains. Compounds 10 and 37 were the most active against S. mutans (MIC: 8 μg/mL), while compounds 11 and 37 showed the highest activity against B. subtillis (MIC: 16 μg/mL), whereas compounds 10, 11 and 37 displayed activities against E. coli (MIC: 16 μg/mL). Meanwhile, compounds 10 and 35 depicted activities against S. typhi (MIC: 16 μg/mL) and compound 10 showed antifungal activity against C. albicans (MIC: 32 μg/mL). The current study has identified two broad-spectrum antibacterial hit compounds (10 and 37). Further structural investigation on these molecules is underway to enhance their potency.

Recent Advances and Techniques for Identifying Novel Antibacterial Targets.

With the emergence of drug-resistant bacteria, the development of new antibiotics is urgently required. Target-based drug discovery is the most frequently employed approach for the drug development process. However, traditional drug target identification techniques are costly and time-consuming. As research continues, innovative approaches for antibacterial target identification have been developed which enabled us to discover drug targets more easily and quickly. In this review, methods for finding drug targets from omics databases have been discussed in detail including principles, procedures, advantages, and potential limitations. The role of phage-driven and bacterial cytological profiling approaches is also discussed. Moreover, current article demonstrates the advancements being made in the establishment of computational tools, machine learning algorithms, and databases for antibacterial target identification. Bacterial drug targets successfully identified by employing these aforementioned techniques are described as well. The goal of this review is to attract the interest of synthetic chemists, biologists, and computational researchers to discuss and improve these methods for easier and quicker development of new drugs.

Friend or Foe: Protein Inhibitors of DNA Gyrase.

DNA gyrase is essential for the successful replication of circular chromosomes, such as those found in most bacterial species, by relieving topological stressors associated with unwinding the double-stranded genetic material. This critical central role makes gyrase a valued target for antibacterial approaches, as exemplified by the highly successful fluoroquinolone class of antibiotics. It is reasonable that the activity of gyrase could be intrinsically regulated within cells, thereby helping to coordinate DNA replication with doubling times. Numerous proteins have been identified to exert inhibitory effects on DNA gyrase, although at lower doses, it can appear readily reversible and therefore may have regulatory value. Some of these, such as the small protein toxins found in plasmid-borne addiction modules, can promote cell death by inducing damage to DNA, resulting in an analogous outcome as quinolone antibiotics. Others, however, appear to transiently impact gyrase in a readily reversible and non-damaging mechanism, such as the plasmid-derived Qnr family of DNA-mimetic proteins. The current review examines the origins and known activities of protein inhibitors of gyrase and highlights opportunities to further exert control over bacterial growth by targeting this validated antibacterial target with novel molecular mechanisms. Furthermore, we are gaining new insights into fundamental regulatory strategies of gyrase that may prove important for understanding diverse growth strategies among different bacteria.