New Class Of Antibacterial Agents Research Articles

DBU promoted Efficient Bioactive Synthesis of Novel 1-(2-methyl-1, 5-diphenyl-1H-pyrrol-3-yl) ethanone derivatives

In an attempt to find new class of antibacterial agents, 1-(2-methyl-1,5-diphenyl-1H-pyrrol-3-yl)ethanone (4a –4j) were successfully synthesized from phenacyl bromide ,substituted aryl amine and aetylacetone in the presence of organic base such as DBU promoted in ethanol under reflux. The synthesized compounds were evaluated by spectroscopic techniques such as 1HNMR, 13CNMR and LCMS and elemental analysis. Derivatives were also evaluated for their antibacterial activity.

Antibacterial Activity and Multi-Targeting Mechanism of Dehydrocorydaline From Corydalis turtschaninovii Bess. Against Listeria monocytogenes.

Listeria monocytogenes is a foodborne pathogen, with relatively low incidence but high case-fatality. Phytochemicals have been recognized as a promising antimicrobial agent as an alternative to synthetic chemicals due to their safety and high efficacy with multi-target sites. This study identified and characterized a novel antibacterial agent, dehydrocorydaline, in the Corydalis turschaninovii rhizome using HPLC-LTQ-Orbitrap-HRMS, and its antibacterial effect with lowest MIC (1 mg/mL) and MBC (2 mg/mL) values. In addition, an in vitro growth kinetic assay, cytoplasmic nucleic acid and protein leakage assay, and observation of morphological changes in bacterial cells supported the strong antibacterial activity. Dehydrocorydaline also displayed effective inhibitory effects on biofilm formation and bacterial motility. In order to investigate the potential antibacterial mechanism of action of dehydrocorydaline against L. monocytogenes, label-free quantitative proteomics was used, demonstrating that dehydrocorydaline has multiple targets for combating L. monocytogenes including dysregulation of carbohydrate metabolism, suppression of cell wall synthesis, and inhibition of bacterial motility. Overall, this study demonstrated that dehydrocorydaline has potential as a natural and effective antibacterial agent with multi-target sites in pathogenic bacteria, and provides the basis for development of a new class of antibacterial agent.

Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis.

Bis-substituted cyclam derivatives have recently emerged as a promising new class of antibacterial agents, displaying excellent activity against drug-resistant Mycobacterium tuberculosis (Mtb) and in vivo efficacy in a zebrafish assay. Herein we report the synthesis and biological activity of new carborane derivatives within this class of antitubercular compounds. The resulting carborane-cyclam conjugates incorporating either hydrophobic closo-1,2-carborane or anionic, hydrophilic nido-7,8-carborane clusters display promising activity in an antibacterial assay employing the virulent Mtb strain H37Rv. The most active of these carborane derivatives exhibit MIC50 values of <1 μM, making them the most active compounds in this unique class of antibacterial cyclams reported to date.

Escalating antimicrobial resistance among Enterobacteriaceae: focus on carbapenemases

ABSTRACT Introduction: Over the past few decades, antimicrobial resistance (AMR) has skyrocketed globally among bacteria within the Family Enterobacteriaceae (i.e. Enterobacter spp, Klebsiella spp, Escherichia coli, Proteus spp, Serratia marcescens, Citrobacter spp, and others). Enterobacteriaceae are intestinal flora and are important pathogens in nosocomial and community settings. Enterobacteriaceae spread easily between humans and may acquire AMR via plasmids or other mobile resistance elements. The emergence and spread of multidrug resistant (MDR) clones have greatly limited therapeutic options. Some infections are untreatable with existing antimicrobials. Areas covered: The authors discuss the escalation of CRE globally, the epidemiology and outcomes of CRE infections, the optimal therapy, and the potential role of several new antimicrobials to combat MDR organisms. An exhaustive search for literature related to Enterobacteriaceae was performed using PubMed, using the following key words: antimicrobial resistance; carbapenemases; Enterobacterales; Enterobacteriaceae; Klebsiella pneumoniae; Escherichia coli; global epidemiology; metallo-β-lactamases; multidrug resistance; New Delhi Metalloproteinase-1 (NDM-1); plasmids Expert opinion: Innovation and development of new classes of antibacterial agents are critical to expand effective therapeutic options. The authors encourage the judicious use of antibiotics and aggressive infection-control measures are essential to minimize the spread of AMR.

Polyphenylglyoxamide-Based Amphiphilic Small Molecular Peptidomimetics as Antibacterial Agents with Anti-Biofilm Activity.

The rapid emergence of drug-resistant bacteria is a major global health concern. Antimicrobial peptides (AMPs) and peptidomimetics have arisen as a new class of antibacterial agents in recent years in an attempt to overcome antibiotic resistance. A library of phenylglyoxamide-based small molecular peptidomimetics was synthesised by incorporating an N-alkylsulfonyl hydrophobic group with varying alkyl chain lengths and a hydrophilic cationic group into a glyoxamide core appended to phenyl ring systems. The quaternary ammonium iodide salts 16d and 17c showed excellent minimum inhibitory concentration (MIC) of 4 and 8 μM (2.9 and 5.6 μg/mL) against Staphylococcus aureus, respectively, while the guanidinium hydrochloride salt 34a showed an MIC of 16 μM (8.5 μg/mL) against Escherichia coli. Additionally, the quaternary ammonium iodide salt 17c inhibited 70% S. aureus biofilm formation at 16 μM. It also disrupted 44% of pre-established S. aureus biofilms at 32 μM and 28% of pre-established E. coli biofilms 64 μM, respectively. A cytoplasmic membrane permeability study indicated that the synthesised peptidomimetics acted via disruption and depolarisation of membranes. Moreover, the quaternary ammonium iodide salts 16d and 17c were non-toxic against human cells at their therapeutic dosages against S. aureus.

Explanation of the Formation of Complexes between Representatives of Oxazolidinones and HDAS-β-CD Using Molecular Modeling as a Complementary Technique to cEKC and NMR.

Molecular modeling (MM) results for tedizolid and radezolid with heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD) are presented and compared with the results previously obtained for linezolid and sutezolid. The mechanism of interaction of chiral oxazolidinone ligands belonging to a new class of antibacterial agents, such as linezolid, tedizolid, radezolid, and sutezolid, with HDAS-β-CD based on capillary electrokinetic chromatography (cEKC), nuclear magnetic resonance (NMR) spectroscopy, and MM methods was described. Principles of chiral separation of oxazolidinone analogues using charged single isomer derivatives of cyclodextrin by the cEKC method were presented, including the selection of the optimal chiral selector and separation conditions, complex stoichiometry, and binding constants, which provided a comprehensive basis for MM studies. In turn, NMR provided, where possible, direct information on the geometry of the inclusion complexes and also provided the necessary structural information to validate the MM calculations. Consequently, MM contributed to the understanding of the structure of diastereomeric complexes, the thermodynamics of complexation, and the visualization of their structures. The most probable mean geometries of the studied supramolecular complexes and their dynamics (geometry changes over time) were determined by molecular dynamics methods. Oxazolidinone ligands have been shown to complex mainly the inner part of cyclodextrin, while the external binding is less privileged, which is consistent with the conclusions of the NMR studies. Enthalpy values of binding of complexes were calculated using long-term molecular dynamics in explicit water as well as using molecular mechanics, the Poisson–Boltzmann or generalized Born, and surface area continuum solvation (MM/PBSA and MM/GBSA) methods. Computational methods predicted the effect of changes in pH and composition of the solution on the strength and complexation process, and it adapted the conditions selected as optimal during the cEKC study. By changing the dielectric constant in the MM/PBSA and MM/GBSA calculations, the effect of changing the solution to methanol/acetonitrile was investigated. A fairly successful attempt was made to predict the chiral separation of the oxazolidinones using the modified cyclodextrin by computational methods.

Synthesis and Antibacterial Activity of New Chalcones Bearing an Imidazo[ 1,2-a]pyridine Moiety

Aim and Objective: Herein, A series of new imidazo[1,2-a]pyridine-chalcone derivatives 3a-m were designed and synthesized to find a new class of antibacterial agents. These compounds were prepared by the aldol condensation of 2-phenylimidazo[1,2-a]pyridine-3-carbaldehyde 2a-b with acetophenone derivatives and other aromatic acetyls. High reaction yields were obtained in a short reaction time, through applying this multi-step pathway. Materials and Methods: In vitro antibacterial activities of the synthesized imidazo[1,2-a]pyridinechalcones were measured against S. aureus, B. subtilis and E. coli with MIC values of 32 -128 μg/mL. Finally, essential structural analyses such as CHN and NMR spectroscopies were used to identify the synthesized chalcones based on imidazo[1,2-a]pyridine derivatives. Results: The results showed that most of the products presented moderate to good antibacterial activities. Compounds 3b, 3d, 3g, 3l and 3m revealed obvious potency against S. aureus, B. subtilis and E. coli with MIC values of 32 μg/mL and 64 μg/mL, which were better when compared with other chalcones. Conclusion: The synthesized antibacterial compounds were obtained with appealing advantages such as high purity, simple pathway, good to excellent yields, inexpensive and easy availability of materials as well as good activities against bacteria. So in this work, a new class of antibacterial chalcones based on imidazo[1,2-a]pyridine has been reported.

Antisense peptide nucleic acid inhibits the growth of KPC-producing Klebsiella pneumoniae strain

Klebsiella pneumoniae causes common and severe hospital- and community-acquired infections with a high incidence of multidrug resistance (MDR) and mortality. In this study, we investigated the ability of the antisense peptide nucleic acids (PNA) conjugated to the (KFF)3K cell-penetrating peptide (CPP) to target the gyrA KPC-producing K. pneumoniae and inhibit bacterial growth in vitro. The inhibitory effect on gyrA gene was evaluated by measuring 16s gene amplification in KPC-producing K. pneumoniae treated with the antisense PNA conjugate. The hemolytic property of the antisense PNA conjugate was accessed toward mice red blood cells. Finally, molecular modeling and dynamics simulations analyses in aqueous solutions were performed to predict the PNA conformation alone in contact with DNA (gyrA gene sequence). PNA was capable of inhibiting bacterial growth at 50 μM, also reducing 16S gene amplification in 96.7%. Besides, PNA presented low hemolytic activity (21.1% hemolysis) at this same concentration. Bioinformatics analysis demonstrated that the structure of the PNA is stable in water without major changes in its secondary structure. The ability of PNA and its conjugated CPP ((KFF)3K) to inhibit bacterial growth demonstrates the potential of this new class of antibacterial agents, encouraging further in vivo studies to confirm its therapeutic efficacy.

Synthesis, characterization and antibacterial activity of water-soluble dye-capped zinc sulphide nanoparticles from waste Zn–C battery

Capped and uncapped zinc sulphide (ZnS) nanoparticles (NPs) were successfully synthesized from used Zn–C battery, while surface was modified with capping agent 1-(carboxymethyl)-4-[(E)-2-(1,2-oxazol-3-yl)ethenyl]pyridin-1-ium. The structural properties of synthesized NPs were investigated using scanning electron microscope, energy-dispersive X-ray spectroscopy, powder X-ray diffraction (XRD), Fourier transform infrared and UV–visible spectroscopy. From XRD studies, cubic zinc blend structure for all the NPs was confirmed, and the crystallite size for uncapped and dye-capped NPs were calculated as 18.1 and 15.2 nm from Scherrer’s equation. Quantum espresso software was used to carry out the density functional theory calculations of dye. These dye-capped ZnS NPs proved to be excellent antibacterial agents and the minimum concentrations of pure ZnS and dye-capped ZnS NPs, which restrain the growth of bacteria, were found to be 0.312 and 0.156 mg ml−1 for S. typhi and 1.25 and 0.625 mg ml−1 for B. subtilis, respectively. The bioactivity data suggest that these organic–inorganic hybrid NPs appeared to be a new class of antibacterial agents.

Copper Clusters: An Effective Antibacterial for Eradicating Multidrug‐Resistant Bacterial Infection In Vitro and In Vivo

AbstractInfections caused by multidrug‐resistant (MDR) bacteria pose a threat to human health worldwide, making new effective antibacterial agents urgently desired. To date, it is still a great challenge to develop new antibiotics for MDR bacteria with clear antibacterial mechanisms. Herein, a novel alternative antibacterial copper clusters (CuCs) molecule is precisely synthesized utilizing an artificially designed theanine peptide. The prepared CuCs exhibit excellent broad‐spectrum antibacterial activity in vitro, including gram‐positive bacteria (methicillin‐resistant Staphylococcus aureus [MRSA], Staphylococcus aureus, and Staphylococcus epidermidis) and gram‐negative bacteria (Escherichia coli and Pseudomonas aeruginosa). The robust antibacterial effect is due to its ability to not only destroy the bacterial wall structure, but also regulate the ratio of GSH/GSSG by inhibiting the activity of glutathione reductase, thus causing the outbreak of reactive oxygen species and ultimately leading to bacterial death. In addition, in vivo studies demonstrate that CuCs can significantly rescue skin wound infections and sepsis in mice caused by MRSA, and has the same therapeutic efficacy as mupirocin ointment and first‐line clinically anchored anti‐MRSA drug vancomycin. Moreover, CuCs exhibit extremely low cytotoxicity to normal mammalian cells compared to silver and platinum clusters. With further development and optimization, CuCs has great potential as a new class of antibacterial agents to fight antibiotic‐resistant pathogens.

Unconventional Antibacterials and Adjuvants.

The need for new classes of antibacterials is genuine in light of the dearth of clinical options for the treatment of bacterial infections. The prodigious discoveries of antibiotics during the 1940s to 1970s, a period wistfully referred to as the Golden Age of Antibiotics, have not kept up in the face of emergence of resistant bacteria in the past few decades. There has been a renewed interest in old drugs, the repurposing of the existing antibiotics and pairing of synergistic antibiotics or of an antibiotic with an adjuvant. Notwithstanding, discoveries of novel classes of these life-saving drugs have become increasingly difficult, calling for new paradigms. We describe, herein, three strategies from our laboratories toward discoveries of new antibacterials and adjuvants using computational and multidisciplinary experimental methods. One approach targets penicillin-binding proteins (PBPs), biosynthetic enzymes of cell-wall peptidoglycan, for discoveries of non-β-lactam inhibitors. Oxadiazoles and quinazolinones emerged as two structural classes out of these efforts. Several hundred analogs of these two classes of antibiotics have been synthesized and fully characterized in our laboratories. A second approach ventures into inhibition of allosteric regulation of cell-wall biosynthesis. The mechanistic details of allosteric regulation of PBP2a of Staphylococcus aureus, discovered in our laboratories, is outlined. The allosteric site in this protein is at 60 Å distance to the active site, whereby ligand binding at the former makes access to the latter by the substrate possible. We have documented that both quinazolinones and ceftaroline, a fifth-generation cephalosporin, bind to the allosteric site in manifestation of the antibacterial activity. Attempts at inhibition of the regulatory phosphorylation events identified three classes of antibacterial adjuvants and one class of antibacterials, the picolinamides. The chemical structures for these hits went through diversification by synthesis of hundreds of analogs. These analogs were characterized in various assays for identification of leads with adjuvant and antibacterial activities. Furthermore, we revisited the mechanism of bulgecins, a class of adjuvants discovered and abandoned in the 1980s. These compounds potentiate the activities of β-lactam antibiotics by the formation of bulges at the sites of septum formation during bacterial replication, which are points of structural weakness in the envelope. These bulges experience rupture, which leads to bacterial death. Bulgecin A inhibits the lytic transglycosylase Slt of Pseudomonas aeruginosa as a likely transition-state mimetic for its turnover of the cell-wall peptidoglycan. Once damage to cell wall is inflicted by a β-lactam antibiotic, the function of Slt is to repair the damage. When Slt is inhibited by bulgecin A, the organism cannot cope with it and would undergo rapid lysis. Bulgecin A is an effective adjuvant of β-lactam antibiotics. These discoveries of small-molecule classes of antibacterials or of adjuvants to antibacterials hold promise in strategies for treatment of bacterial infections.

QcrB in Mycobacterium tuberculosis: The new drug target of antitubercular agents

Drug-resistance in mycobacterial infections is a major global health problem that leads to high mortality and socioeconomic pressure in developing countries around the world. From finding new targets to discovering novel chemical scaffolds, there is an urgent need for the development of better approaches for the cure of tuberculosis. Recently, energy metabolism in mycobacteria, particularly the oxidative phosphorylation pathway of cellular respiration, has emerged as a novel target pathway in drug discovery. New classes of antibacterials which target oxidative phosphorylation pathway either by interacting with a protein or any step in the pathway of oxidative phosphorylation can combat dormant mycobacterial infections leading to shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one such recently discovered target of the newly approved antitubercular drug bedaquiline. Cytochrome bcc is another new target of the antitubercular drug candidate Q203, currently in phase II clinical trial. Research suggests that b subunit of cytochrome bcc, QcrB, is the target of Q203. The review article describes the structure, function, and importance of targeting QcrB throwing light on all chemical classes of QcrB inhibitors discovered to date. An understanding of the structure and function of validated targets and their inhibitors would enable the development of new chemical entities.

Recent Advances in 1,3,5-Triazine Derivatives as Antibacterial Agents

Triazine, one of the nitrogen containing heterocyclic compounds has attracted the considerable interest of researchers due to the vast array of biological properties such as anti-viral, antitumor, anti-convulsant, analgesic, antioxidant, anti-depressant, herbicidal, insecticidal, fungicidal, antibacterial and anti-inflammatory activities offered by it. Various antibacterial agents have been synthesized by researchers to curb bacterial diseases but due to rapid development in drug resistance, tolerance and side effects, there had always been a need for the synthesis of a new class of antibacterial agents that would exhibit improved pharmacological action. Therefore, this review mainly focuses on the various methods for the synthesis of triazine derivatives and their antibacterial activity.

1,2,3-Triazole-containing hybrids with potential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA), as a classic reason for genuine skin and flimsy tissues diseases, is a worldwide general wellbeing risk and has already tormented humanity for a long history, creating a critical need for the development of new classes of antibacterials. 1,2,3-Triazole moiety, readily interact with diverse enzymes and receptors in organisms through weak bond interaction, is among the most common frameworks present in the bioactive molecules. 1,2,3-Triazole derivatives, especially 1,2,3-triazole-containing hybrids, possess broad-spectrum activity against a panel of clinically important bacteria including drug-resistant pathogens, so rational design of 1,2,3-triazole derivatives may open a door for the opportunities on the development of novel anti-MRSA agents. This review is an endeavour to highlight the current scenario of 1,2,3-triazole-containing hybrids with potential anti-MRSA activity, covering articles published between 2010 and 2020.

Exploitation of Pare Topoisomerase IV as Drug Target for the Treatment of Multidrug-Resistant Bacteria: A Review

The antibacterial resistance (ABR) is a growing phenomenon and global threat to mankind. To circumvent the ABR, many approaches have been put forth, but none of them meet the pre-requisites associated with the resistance mechanisms. In this review, we focused on the importance of unexploited enzyme, ParE, a topoisomerase responsible for the bacterial survival. The bacterial topoisomerases maintain the topological state of DNA. The gyrases and topoisomerases IV are validated targets for the antibacterial activity. Both these enzymes are structurally similar and possess high degree conservation in the catalytic domain of the N-terminal region, which make them appealing targets for broad spectrum antibacterial activity. Despite being an attractive target for the development of new antibacterials, there are currently no antibiotics targeting gyrases and topoisomerase (topo) IV in the market. Availability of the high-resolution crystal structure data for ParE made it possible to design new classes of antibacterials. Here, we discuss the importance of targeting topo IV enzyme as it is less prone to bacterial resistance which has been disclosed in the literature.

Synthesis and assessment of bisindoles as a new class of antibacterial agents

Antimicrobial screening of an in-house library containing both natural products and synthetic compounds identified a bisindole molecule as a selective antibacterial hit. Further evaluation and structural modification afforded a series of dimeric indole derivatives, most of which showed moderate to good antibacterial activity against two Gram-positive strains Staphylococcus aureus and Bacillus subtilis. Chiral HPLC was employed to separate these racemates and the bioactive differences between the enantiomeric pairs were also assessed and discussed. Three dihalogenaged analogues also showed mild growth inhibition against a drug-resistant S. aureus strain.

Crystal structure of Haemophilus influenzae 3-isopropylmalate dehydrogenase (LeuB) in complex with the inhibitor O-isobutenyl oxalylhydroxamate

3-isopropylmalate dehydrogenases (LeuB) belong to the leucine biosynthetic pathway and catalyze the irreversible oxidative decarboxylation of 3IPM to 2-ketoisocaproate that is finally converted into leucine by a branched-chain aminotransferase. Since leucine is an essential amino acid for humans, and it is also vital for the growth of many pathogenic bacteria, the enzymes belonging to this pathway can be considered as potential target sites for designing of a new class of antibacterial agents. We have determined the crystal structure of the Haemophilus influenzae LeuB in complex with the cofactor NAD+ and the inhibitor O-IbOHA, at 2.1 Å resolution; moreover, we have investigated the inhibitor mechanism of action by analyzing the enzyme kinetics. The structure of H. influenzae LeuB in complex with the intermediate analog inhibitor displays a fully closed conformation, resembling the previously observed, closed form of the equivalent enzyme of Thiobacillus ferrooxidans in complex with the 3IPM substrate. O-IbOHA was found to bind the active site by adopting the same conformation of 3IPM, and to induce an unreported repositioning of the side chain of the amino acids that participate in the coordination of the ligand. Indeed, the experimentally observed binding mode of O-IbOHA to the H. influenzae LeuB enzyme, reveals aspects of novelty compared to the computational binding prediction performed on M. tuberculosis LeuB. Overall, our data provide new insights for the structure-based rational design of a new class of antibiotics targeting the biosynthesis of leucine in pathogenic bacteria.

From Substrate to Fragments to Inhibitor Active In Vivo against Staphylococcus aureus.

Antibiotic resistance is a worldwide threat due to the decreasing supply of new antimicrobials. Novel targets and innovative strategies are urgently needed to generate pathbreaking drug compounds. NAD kinase (NADK) is essential for growth in most bacteria, as it supports critical metabolic pathways. Here, we report the discovery of a new class of antibacterials that targets bacterial NADK. We generated a series of small synthetic adenine derivatives to screen those harboring promising substituents in order to guide efficient fragment linking. This led to NKI1, a new lead compound inhibiting NADK that showed in vitro bactericidal activity against Staphylococcus aureus. In a murine model of infection, NKI1 restricted survival of the bacteria, including methicillin-resistant S.aureus. Collectively, these findings identify bacterial NADK as a potential drug target and NKI1 as a lead compound in the treatment of staphylococcal infections.

N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification

Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 μg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25–1 μg/mL vs. 1–64 μg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6–155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.

Covalent Functionalization of Graphene Sheets with Different Moieties and Their Effects on Biological Activities.

The ongoing spread of multi-drug-resistant bacteria over the past few decades necessitates collateral efforts to develop new classes of antibacterial agents with different mechanisms of action. The utilization of graphene nanosheets has recently gained attention with this respect. Herein, we have synthesized and tested the antibacterial activity of an array of graphene materials covalently functionalized with hydroxyl-, amine-, or carboxyl-containing groups. Fourier transform infrared spectroscopy and transmission electron microscopy confirmed successful functionalization of the few-layer graphene (FLG). The percentage of weight loss was measured by thermogravimetric analysis, which was found to be 22%, 23%, and 37% for FLG-TEG-OH, FLG-NH2, and FLG-DEG-COOH, respectively. In comparison with pristine graphene sheets, the functionalized few-layer graphene (f-FLG) materials gained an adequate dispersibility in water as confirmed by ζ potential analysis. Moreover, there was a significant improvement in the antibacterial activity against Staphylococcus aureus and Escherichia coli, where all f-FLG compounds were able to suppress bacterial growth, with a complete suppression achieved by FLG-DEG-COOH. The minimum inhibitory concentration (MIC) was 250 μg mL-1 for both FLG-TEG-OH and FLG-NH2, while it was 125 μg mL-1 for FLG-DEG-COOH. The glutathione oxidation test demonstrated an oxidative stress activity by all f-FLG compounds. However, FLG-DEG-COOH demonstrated the highest reduction in glutathione activity. FLG-DEG-COOH and FLG-TEG-OH showed adequate biocompatibility and hemocompatibility. The chemical functionalization of graphene might be a step toward the foundation of an effective class of antimicrobial agents.