Antimicrobial Potential of Chiral Amide Derivatives of Ricinoleic and 3-Hydroxynonanoic Acid

The growing role of fatty acid amides in medicinal chemistry has recently been observed. Therefore, using simple and fast methods, a series of chiral amide derivatives (24 compounds) of ricinoleic and 3-hydroxynonanoic acid was obtained with 31–95% yields. Then, the evaluation of their antimicrobial activity against 13 microorganisms representing Gram-positive and Gram-negative bacteria, yeast, and molds was performed. The obtained compounds showed antimold potential; however, the tested species of molds were more susceptible to derivatives of 3-hydroxynonanoic acid than to amides obtained from ricinoleic acid (RA). Interestingly, hydroxamic acids derived from RA exhibited the best activity against Candida albicans and Candida tropicalis. On the other hand, hydroxamic acids derived from 3-hydroxynonanoic acid showed the best antimicrobial potential against the remaining tested microorganisms, especially against Pseudomonas cedrina. The obtained derivatives can be considered compounds of potential pharmacological significance, which is important due to the increasing problem of microbial resistance.     

Potent Activity of Hybrid Arthropod Antimicrobial Peptides Linked by Glycine Spacers

Arthropod antimicrobial peptides (AMPs) offer a promising source of new leads to address the declining number of novel antibiotics and the increasing prevalence of multidrug-resistant bacterial pathogens. AMPs with potent activity against Gram-negative bacteria and distinct modes of action have been identified in insects and scorpions, allowing the discovery of AMP combinations with additive and/or synergistic effects. Here, we tested the synergistic activity of two AMPs, from the dung beetle Copris tripartitus (CopA3) and the scorpion Heterometrus petersii (Hp1090), against two strains of Escherichia coli. We also tested the antibacterial activity of two hybrid peptides generated by joining CopA3 and Hp1090 with linkers comprising two (InSco2) or six (InSco6) glycine residues. We found that CopA3 and Hp1090 acted synergistically against both bacterial strains, and the hybrid peptide InSco2 showed more potent bactericidal activity than the parental AMPs or InSco6. Molecular dynamics simulations revealed that the short linker stabilizes an N-terminal 3₁₀-helix in the hybrid peptide InSco2. This secondary structure forms from a coil region that interacts with phosphatidylethanolamine in the membrane bilayer model. The highest concentration of the hybrid peptides used in this study was associated with stronger hemolytic activity than equivalent concentrations of the parental AMPs. As observed for CopA3, the increasing concentration of InSco2 was also cytotoxic to BHK-21 cells. We conclude that AMP hybrids linked by glycine spacers display potent antibacterial activity and that the cytotoxic activity can be modulated by adjusting the nature of the linker peptide, thus offering a strategy to produce hybrid peptides as safe replacements or adjuncts for conventional antibiotic therapy.     

Motuporamine Derivatives as Antimicrobial Agents and Antibiotic Enhancers against Resistant Gram‐Negative Bacteria

Dihydromotuporamine C and its derivatives were evaluated for their in vitro antimicrobial activities and antibiotic enhancement properties against Gram‐negative bacteria and clinical isolates. The mechanism of action of one of these derivatives, MOTU‐N44, was investigated against Enterobacter aerogenes by using fluorescent dyes to evaluate outer‐membrane depolarization and permeabilization. Its efficiency correlated with inhibition of dye transport, thus suggesting that these molecules inhibit drug transporters by de‐energization of the efflux pump rather than by direct interaction of the molecule with the pump. This suggests that depowering the efflux pump provides another strategy to address antibiotic resistance.     

Antioxidant and Biological Activities of Novel Structured Monoacylglycerol Derivatives with Phenolic Acids

Novel structured monoacylglycerol (MAG)-based phenolic lipids are synthesized from11-bromoundecanoic acid, phenolic acids, and solketal. Selected phenolic acids namely 4-hydroxy benzoic, vanillic, syringic, cinnamic, p-coumaric, sinapic, 4-fluorocinnamic, 4-hydroxyphenyl acetic acid, 3-(4-hydroxyphenyl) propanoic and dihydrocaffeic acids are employed for the synthesis of ten novel MAG-based phenolic lipids. The synthesized phenolic lipids are characterized by FT-IR, NMR, and mass spectra analysis. All the compounds are evaluated for antioxidant, antimicrobial, and cytotoxic activities. MAG derivative 8g of sinapic acid exhibits excellent antioxidant activity in both DPPH assay and inhibition of lipid oxidation assay. MAG derivative 8f bearing p-coumaric acid shows good antimicrobial activity against both Gram-positive and Gram-negative bacterial strains with a minimum inhibitory concentration (MIC) value of 6.25 µm mL⁻¹. All the synthesized compounds are found to exhibit cytotoxicity against B16, DU145, and CHO cell lines, while sinapic and p-coumaric acid derivatives exhibit better activities compared to other derivatives.     

Development of direct contact-killing non-leaching antimicrobial polyurethanes through click chemistry

A robust, efficient, and orthogonal click chemistry (copper (I)-catalyzed alkyne-azide cycloaddition) was used to prepare an antimicrobial polymer and precisely control the conjugation ratio of antibiotic molecules to polymer. Antimicrobial polyurethanes with pendant benzisothiazolinone (PU-BIT) were synthesized using click chemistry to connect azide functional polyurethane (PU-N₃) and alkyne functional benzisothiazolinone (BIT-Al). The direct contact-killing and non-leaching antimicrobial properties of PU-BIT were verified by both antimicrobial drop and disk diffusion. This approach provides a new methodology and platform for the development of contact-killing and non-leaching antimicrobial materials for a variety of practical applications. This research is the first to demonstrate that the broad-spectrum BIT antibiotic is a selective antibiotic for Gram-positive bacteria when covalently linked to a polymer. PU-BIT film containing 0.8 wt% BIT exhibited a selective antimicrobial performance with bactericidal efficacy of 91.6% and 30% against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, respectively. The mechanism of the selective antimicrobial activity of PU-BIT is also discussed.     

Strategies to Tackle Antimicrobial Resistance: The Example of Escherichia coli and Pseudomonas aeruginosa

Traditional antimicrobial treatments consist of drugs which target different essential functions in pathogens. Nevertheless, bacteria continue to evolve new mechanisms to evade this drug-mediated killing with surprising speed on the deployment of each new drug and antibiotic worldwide, a phenomenon called antimicrobial resistance (AMR). Nowadays, AMR represents a critical health threat, for which new medical interventions are urgently needed. By 2050, it is estimated that the leading cause of death will be through untreatable AMR pathogens. Although antibiotics remain a first-line treatment, non-antibiotic therapies such as prophylactic vaccines and therapeutic monoclonal antibodies (mAbs) are increasingly interesting alternatives to limit the spread of such antibiotic resistant microorganisms. For the discovery of new vaccines and mAbs, the search for effective antigens that are able to raise protective immune responses is a challenging undertaking. In this context, outer membrane vesicles (OMV) represent a promising approach, as they recapitulate the complete antigen repertoire that occurs on the surface of Gram-negative bacteria. In this review, we present Escherichia coli and Pseudomonas aeruginosa as specific examples of key AMR threats caused by Gram-negative bacteria and we discuss the current status of mAbs and vaccine approaches under development as well as how knowledge on OMV could benefit antigen discovery strategies.     

Expanding the Spectrum of Antibiotics Capable of Killing Multidrug-Resistant Staphylococcus aureus and Pseudomonas aeruginosa

Infections from antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa are a serious threat because reduced antibiotic efficacy complicates treatment decisions and prolongs the disease state in many patients. To expand the arsenal of treatments against antimicrobial-resistant (AMR) pathogens, 600-Da branched polyethylenimine (BPEI) can overcome antibiotic resistance mechanisms and potentiate β-lactam antibiotics against Gram-positive bacteria. BPEI binds cell-wall teichoic acids and disables resistance factors from penicillin binding proteins PBP2a and PBP4. This study describes a new mechanism of action for BPEI potentiation of antibiotics generally regarded as agents effective against Gram-positive pathogens but not Gram-negative bacteria. 600-Da BPEI is able to reduce the barriers to drug influx and facilitate the uptake of a non-β-lactam co-drug, erythromycin, which targets the intracellular machinery. Also, BPEI can suppress production of the cytokine interleukin IL-8 by human epithelial keratinocytes. This enables BPEI to function as a broad-spectrum antibiotic potentiator, and expands the opportunities to improve drug design, antibiotic development, and therapeutic approaches against pathogenic bacteria, especially for wound care.     

Modification of narrow‐spectrum peptidomimetic polyurethanes with fatty acid chains confers broad‐spectrum antibacterial activity

Each year, thousands of patients die from antimicrobial‐resistant bacterial infections that fail to respond to conventional antibiotic treatment. Antimicrobial polymers are a promising new method of combating antibiotic‐resistant bacterial infections. We have previously reported the synthesis of a series of narrow‐spectrum peptidomimetic antimicrobial polyurethanes that are effective against Gram‐negative bacteria, such as Escherichia coli; however, these polymers are not effective against Gram‐positive bacteria, such as Staphylococcus aureus. With the aim of understanding the correlation between chemical structure and antibacterial activity, we have subsequently developed three structural variants of these antimicrobial polyurethanes using post‐polymerization modification with decanoic acid and oleic acid. Our results show that such modifications converted the narrow‐spectrum antibacterial activity of these polymers into broad‐spectrum activity against Gram‐positive species such as S. aureus, however, also increasing their toxicity to mammalian cells. Mechanistic studies of bacterial membrane disruption illustrate the differences in antibacterial action between the various polymers. The results demonstrate the challenge of balancing antimicrobial activity and mammalian cell compatibility in the design of antimicrobial polymer compositions. © 2019 Society of Chemical Industry     

Synthesis and biological activities of 3-polyamino-5β-cholane-7α,24-diols

A series of 3-polyaminochenodeoxycholic acid derivatives were synthesized and their in vitro antimicrobial and antifungal activities were assessed. The antimicrobial activity was evaluated against Gram-positive and Gram-negative bacteria, and the antifungal activity was assessed against two strains Candida albicans (ATCC MYA-1003) and Aspergillus fumigatus (ATCC 16424). The introduction of an amine group to steroid was accomplished by reductive amination of 3-oxosteroid 9 with Boc-spermidine and Boc-spermine, in the presence of NaBH(OAc)₃. This afforded a high yield of 3-polyaminosteroids of 10–13. The 3β-sperminyl-5β-cholane 6 showed the highest antimicrobial activity against Streptococcus pyogenes 308A, Staphylococcus aureus 503, Escherichia coli DC2 and Pseudomonas aeruginosa 9027 with a MIC value of 3.13 μg/mL.     

Antimicrobial and Cytotoxic Properties of Bisquaternary Ammonium Bromides of Different Spacer Length

A group of cationic gemini surfactants (bisquaternary ammonium bromides) with different spacer chain lengths (8–6–8, 8–7–8, 8–8–8, 8–9–8) was investigated, paying special attention to antimicrobial and the cytotoxic properties as well as their antimicrobial activity during long‐term storage. It was shown that the compounds investigated exhibit excellent antimicrobial activity against Gram‐positive bacteria (Staphylococcus aureus) and Gram‐negative bacteria (Pseudomonas aeruginosa) as well as antifungal properties (Candida albicans). The gemini surfactants tested had the differential level of cytotoxicity against normal lymphocytes. It was shown that the spacer chain length plays an important role in antibacterial activity and influences the cytotoxicity. The gemini surfactants with shorter spacer chain length, that had higher critical micelle concentration, showed generally weaker antibacterial properties, but on the other hand, these exhibited lower level of cytotoxicity. Furthermore, the aqueous solution of gemini surfactants exhibited the same antimicrobial activity even after 3 months.     

Effect of Amino Acid Substitutions on 70S Ribosomal Binding,Cellular Uptake,and Antimicrobial Activity of Oncocin Onc112

Proline-rich antimicrobial peptides (PrAMPs) are promising candidates for the treatment of infections caused by high-priority human pathogens. Their mode of action consists of (I) passive diffusion across the outer membrane, (II) active transport through the inner membrane, and (III) inhibition of protein biosynthesis by blocking the exit tunnel of the 70S ribosome. We tested whether in vitro data on ribosomal binding and bacterial uptake could predict the antibacterial activity of PrAMPs against Gram-negative and Gram-positive bacteria. Ribosomal binding and bacterial uptake rates were measured for 47 derivatives of PrAMP Onc112 and compared to the minimal inhibitory concentrations (MIC) of each peptide. Ribosomal binding was evaluated for ribosome extracts from four Gram-negative bacteria. Bacterial uptake was assessed by quantifying each peptide in the supernatants of bacterial cultures. Oncocin analogues with a higher net positive charge appeared to be more active, although their ribosome binding and uptake rates were not necessarily better than for Onc112. The data suggest a complex mode of action influenced by further factors improving or reducing the antibacterial activity, including diffusion through membranes, transport mechanism, secondary targets, off-target binding, intracellular distribution, and membrane effects. Relying only on in vitro binding and uptake data may not be sufficient for the rational development of more active analogues.     

Chemoenzymatic synthesis and antimicrobial and haemolytic activities of amphiphilic bis(phenylacetylarginine) derivatives

Novel bis(N(alpha)-phenylacetyl-L-arginine)-alpha,omega-alkanediamide dihydrochloride (bis(PhAcArg)) derivatives with antimicrobial activity were designed and synthesised by a chemoenzymatic strategy. The new structures consist of two N(alpha)-phenylacetyl-L-arginine moieties connected by an alkanediamine spacer chain of 6, 8, 10, 12, and 14 methylene units through amide bonds. The key step in the chemoenzymatic strategy is the double aminolysis of the N(alpha)-phenylacetyl-L-arginine methyl ester by the corresponding alpha,omega-alkanediamine catalyzed by papain in ethanolic media. The compounds synthesised were tested as antimicrobials against 15 bacterial and 8 fungal species. The antimicrobial activity and selectivity depend strongly on the spacer chain length. The bis(PhAcArg) derivative with the spacer chain of 12 methylene groups gave the lowest MIC values against Gram-positive bacteria, whereas that with 14 methylene units was the best against Gram-negative bacteria. Interestingly, these novel compounds showed enhanced antibacterial activity relative to the lead compound, bis(N(alpha)-caproyl-L-arginine)-1,3-propanediamide dihydrochloride (C(3)(CA)(2)), and moderate antifungal activity. Moreover, tests of haemolytic activity toward human erythrocytes revealed that haemolysis increases with spacer chain length. Importantly, the compounds were classified as not irritating to eyes, with the exception of the compound with the spacer chain of 14 methylene groups, which was a slight eye irritant.     

Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7–23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14–16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7–23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal “dual action” for β-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro.     

Size-dependent antimicrobial properties of sugar-encapsulated gold nanoparticles synthesized by a green method

The antimicrobial properties of dextrose-encapsulated gold nanoparticles (dGNPs) with average diameters of 25, 60, and 120 nm (± 5) and synthesized by green chemistry principles were investigated against both Gram-negative and Gram-positive bacteria. Studies were performed involving the effect of dGNPs on the growth, morphology, and ultrastructural properties of bacteria. dGNPs were found to have significant dose-dependent antibacterial activity which was also proportional to their size. Experiments revealed the dGNPs to be bacteriostatic as well as bactericidal. The dGNPs exhibited their bactericidal action by disrupting the bacterial cell membrane which leads to the leakage of cytoplasmic content. The overall outcome of this study suggests that green-synthesized dGNPs hold promise as a potent antibacterial agent against a wide range of disease-causing bacteria by preventing and controlling possible infections or diseases.     

Towards the Prediction of Antimicrobial Efficacy for Hydrogen Bonded,Self-Associating Amphiphiles

Herein we report 50 structurally related supramolecular self-associating amphiphilic (SSA) salts and related compounds. These SSAs are shown to act as antimicrobial agents, active against model Gram-positive (methicillin-resistant Staphylococcus aureus) and/or Gram-negative (Escherichia coli) bacteria of clinical interest. Through a combination of solution-state, gas-phase, solid-state and in silico measurements, we determine 14 different physicochemical parameters for each of these 50 structurally related compounds. These parameter sets are then used to identify molecular structure-physicochemical property-antimicrobial activity relationships for our model Gram-negative and Gram-positive bacteria, while simultaneously providing insight towards the elucidation of SSA mode of antimicrobial action.     

Macrocyclic hairpin mimetics of the cationic antimicrobial peptide protegrin I: a new family of broad-spectrum antibiotics

The problems associated with increasing antibiotic resistance have stimulated great interest in newly discovered families of naturally occurring cationic antimicrobial peptides. These include protegrin, tachyplesin, and RTD-1, which adopt beta-hairpin-like structures. We report here an approach to novel peptidomimetics based on these natural products. The mimetics were designed by transplanting the cationic and hydrophobic residues onto a beta-hairpin-inducing template, either a D-Pro-L-Pro dipeptide or a xanthene derivative. The mimetics have good antimicrobial activity against Gram-positive and Gram-negative bacteria (minimal inhibitory concentration approximately 6-25 microgram mL(-1)). Analogues with improved selectivity for microbial rather than red blood cells (1 % hemolysis at 100 microgram mL(-1)) were identified from a small library prepared by parallel synthesis. Thus, it is possible to separate the antimicrobial and hemolytic activities in this class of mimetics. NMR studies on one mimetic revealed a largely unordered structure in water, but a transition to a regular beta-hairpin backbone conformation in the presence of dodecylphosphocholine micelles. This family of mimetics may provide a starting point for the optimization of antimicrobial agents of potential clinical value in the fight against multiple-drug-resistant microorganisms.     

1-烷基吲哚-3-乙酸的合成

以吲哚-3-乙腈为原料,经过与卤代烷在碱存在下的N-烷基化和碱水解2步反应分别合成了1-甲基吲哚-3-乙酸(2a)和1-[3-(四氢-2H-吡喃-2-氧基)丙基]-1H-吲哚-3-乙酸(2b),总收率分别为87%和68%,其结构经1H NMR和Ms确证。     

N-取代吲哚-3-甲醇的合成

首先由吲哚、三氯氧磷和N,N-二甲基甲酰胺通过Vilsmeier-Haack反应合成吲哚-3-甲醛,产率为97%;进而选择二甲亚砜-氢氧化钠反应体系,室温下由碘甲烷、烯丙基溴、溴化苄和甲苯-4-磺酰氯分别对吲哚-3-甲醛进行N-取代,合成4种N-取代吲哚-3-甲醛——N-甲基吲哚-3-甲醛、N-烯丙基吲哚-3-甲醛、N-苄基吲哚-3-甲醛和N-对甲苯磺酰基吲哚-3-甲醛,产率分别为89%、95%、83%和81%;最后选择硼氢化钠为还原剂,室温下通过还原反应合成吲哚-3-甲醇以及4种N-取代吲哚-3-甲醇——N-甲基吲哚-3-甲醇、N-烯丙基吲哚-3-甲醇、N-苄基吲哚-3-甲醇和N-对甲苯磺酰基吲哚-3-甲醇,产率分别为80%、90%、81%、63%和53%。中间产物及终产物的结构经由1HNMR、IR和元素分析证实。     

Synthesis of some novel 2-oxo-pyrano(2,3-b)- and 2-oxo-pyrido(2,3-b)quinoline derivatives as potential antimalarial,diuretic, clastogenic and antimicrobial agents

The 2-chloro-3-formyl quinoline derivatives ( 1a–e ) on treatment with acetic anhydride and sodium acetate, afforded the corresponding novel 2-oxo-pyrano(2,3-b) quinoline derivatives ( 2a–e ), and these were subjected to ammonia treatment to yield the corresponding naphthyridine derivatives ( 3a–e ). The prepared compounds ( 2a–e ) were tested for their antimalarial, diuretic, clastogenic and antimicrobial properties. Not all the compounds showed a diuretic effect and the significant increase in the frequency of micronuclei shows that they are non-clastogens, whereas the 7-chloro derivative ( 2e ) was a very effective antimalarial agent against the mosquito species. All the compounds were found to have optimum antimicrobial activity against Staphylococcus aureus, Escherichia coli and Salmonella typhi. Compounds 2d and 2e were found to be most active against the bacteria tested. © 1998 SCI