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     

Non‐natural Acetogenin Analogues as Potent Trypanosoma brucei Inhibitors

Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis‐tetrahydropyran 1,4‐triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4‐triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure–activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti‐HAT agents.     

Polymerized ionic liquids-based hydrogels with intrinsic antibacterial activity: Modern weapons against antibiotic-resistant infections

In this study, the inherent antibacterial activity of 11 different polymerized ionic liquids (PILs)-based hydrogels as well as their corresponding monomers was examined in an extensive screening. The methicillin-resistant Staphylococcus aureus Xen 30 (MRSA Xen 30) and Pseudomonas aeruginosa Xen 5 (P. aeruginosa Xen 5) were chosen as test microorganisms. Both are typical representatives of gram-positive and gram-negative bacteria, respectively. Six of the 11 tested monomers were able to eradicate more than 80% of P. aeruginosa Xen 5 cells in suspension. Unfortunately, the anionic, neutral and zwitterionic representatives lost their function after polymerization. However, the cationic gels retained their antibacterial activity with nearly 100% eradication of selected microorganisms - even at the smallest amount tested. Bactericidal activity against gram-positive MRSA Xen 30 was high when the bacteria were treated with the imidazolium-based monomers. Five of the tested compounds showed rather limited bactericidal activity <50% killed bacteria. The weak antibacterial activities could be significantly increased by crosslinking them to three-dimensional networks. As a result, all the hydrogels possessed strong killing efficiencies of at least 68% and were able to maintain this activity even at low hydrogel volume fractions. These findings are very promising for the development of new antibacterial materials for medical applications, for example, stent coatings.     

Durable antibacterial finish on cotton fabric by using chitosan‐based polymeric core‐shell particles

Cotton fabric with excellent antibacterial durability was obtained when treated with chitosan‐containing core‐shell particles without any chemical binders. These amphiphilic nanosized particles with antibacterial chitosan shells covalently grafted onto polymer cores were prepared via a surfactant‐free emulsion copolymerization in aqueous chitosan. Herein, two core‐shell particles, one with poly(n‐butyl acrylate) soft core and another with crosslinked poly(N‐isopropylamide) hard core, were synthesized and applied to cotton fabric by a conventional pad‐dry‐cure process. Antimicrobial activity was evaluated quantitatively using a Shake Flask Method in which the reduction of the number of Staphylococcus aureus cells was counted. The results showed that treated fabric had an excellent antibacterial property with bacterial reduction higher than 99%. The antibacterial activity maintained at over 90% reduction level even after 50 times of home laundering. The fabric surface morphology as well as the effect of latex particles with different core flexibilities on fabric hand, air permeability, break tensile strength, and elongation was investigated. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 1787–1793, 2006     

Effect of Ester to Amide or N‐Methylamide Substitution on Bacterial Membrane Depolarization and Antibacterial Activity of Novel Cyclic Lipopeptides

Cyclic lipopeptides derived from the fusaricidin/LI‐F family of naturally occurring antibiotics represent particularly attractive candidates for the development of new antibacterial agents. In comparison with natural products, these derivatives may offer better stability under physiologically relevant conditions and lower nonspecific toxicity, while preserving their antibacterial activity. In this study we assessed the ability of cyclic lipodepsipeptide 1 and its analogues—amide 2 , N‐methylamide 3 , and linear peptide 4 —to interact with the cytoplasmic membranes of selected Gram‐positive bacteria. We also investigated their bacteriostatic/bactericidal modes of action and in vivo potency by using a Galleria mellonella model of MRSA infection. Cyclic lipopeptides 1 and 2 depolarize the cytoplasmic membranes of Gram‐positive bacteria in a concentration‐dependent manner. The degree of membrane depolarization was influenced by the structural and physical properties of 1 and 2 , with the more flexible and hydrophobic peptide 1 being most efficient. However, membrane depolarization does not correlate with bacterial cell lethality, suggesting that membrane‐targeting activity is not the main mode of action for this class of antibacterial peptides. Conversely, substitution of the depsipeptide bond in 1 with an N‐methylamide bond in 3 , or its hydrolysis to peptide 4 , lead to a complete loss of antibacterial activity and indicate that the conformation of cyclic lipopeptides plays a role in their antibacterial activities. Cyclic lipopeptides 1 and 2 are also capable of improving the survival of G. mellonella larvae infected with MRSA at varying efficiencies, reflecting their in vitro activities. Gaining more insight into the structure–activity relationship and mode of action of these cyclic lipopeptides may enable the development of new antibiotics of this class with improved antibacterial activity.     

Alcohol Dehydrogenase‐Catalyzed Synthesis of Enantiomerically Pure δ‐Lactones as Versatile Intermediates for Natural Product Synthesis

Starting from ethyl 4‐bromobutyrate, the chemoenzymatic synthesis of 6‐vinyl‐tetrahydro‐pyran‐2‐one has been accomplished. A screening of a number of available alcohol dehydrogenases and intense optimization of reaction parameters enabled us to establish an efficient synthesis of either enantiomer of the vinyllactone with excellent enantiomeric excess (>99%). The scope of possible applications of enantiopure vinyllactones has been verified by subjection to cross‐metathesis resulting in the total synthesis of the insect pheromone (S)‐5‐hexadecanolide and the cytotoxic styryllactone goniothalamine as well as derivatives thereof.     

Studies in the development of antibacterial surfactants. II. performance of germicidal and deodorant soaps

Summary It has been shown that mixtures of hexachlorophene and trichlorocarbanilide or bithionol and trichlorocarbanilide in soap show a marked synergism with respect to antibacterial properties. In both cases the approximate ratio of 50/50 of the two components represents an optimum. Nonionic detergents enhance the antibacterial activity of trichlorocarbanilidein vitro when present at relatively low levels. At higher levels of nonionic the antibacterial agent is neutralized and loses its effectiveness. The antibacterial activity of the pair hexachlorophene-trichlorocarbanilide extends over a wide spectrum of micro-organisms, and synergism is shown with each test organism. High antibacterial activity of the synergistic pairs in soap is shown both inin vivo handwashing studies and in subjective deodorant tests. On the other hand, it is shown by way of several examples thatin vivo observations do not necessarily correlate within vitro bacteriological screening tests.     

Short Photoswitchable Antibacterial Peptides

Three photoswitchable tetrapeptides, based on a known synthetic antibacterial, were designed and synthesized to determine activity against Staphylococcus aureus. Each peptide contains an azobenzene photoswitch incorporated into either the N-terminal side chain ( 1 ), C-terminal side chain ( 2 ), or the C-terminus ( 3 ) to allow reversible switching between cis- and trans-enriched photostationary states. Biological assays revealed that the C-terminus azobenzene ( 3 ) possessed the most potent antibacterial activity, with an MIC of 1 μg/mL. In this study, net positive charge, hydrophobicity, position of the azobenzene, secondary structure, and amphiphilicity were all found to contribute to antibacterial activity, with each of these factors likely facilitating the peptide to disrupt the negatively charged bacterial lipid membrane. Hence, these short photoswitchable antibacterial tetrapeptides provide insights for the future design and synthesis of antibiotics targeting S. aureus.     

Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ-Diamino Acids

Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS β-turn region is replaced by synthetic β,γ-diamino acids (β,γ-DiAAs). Four β,γ-DiAA diastereomers were employed to mimic the β-turn structure to afford GS analogues GS 3 – 6 , which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (βR,γS)-DiAA is the most-stable β-turn mimic. To further improve the therapeutic index (e. g., high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS 5 and GS 6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS 6K , GS 6F and GS display comparable antibacterial activity, and GS 6K and GS 6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS 6K kills bacteria mainly through the disruption of the membrane.     

Core-crosslinking as a pathway to develop inherently antibacterial polymeric micelles

Positively charged polymeric materials have been an alternative to combat bacteria as they exhibit inherently antibacterial potency via bacteria membrane disruption. In this study, we report facile preparation of positively charged core-crosslinked polymeric micelles with inherent antibacterial properties. Spherical micelles were prepared by self-assembling of poly(4-vinylpyridine)-b-(oligoethylene glycol methyl ether methacrylate) copolymer in aqueous solution. Herein, quaternization reaction was utilized for the first time to core crosslink the micelles through the pyridine rings utilizing their hydrophobic core and thus resulting positively charged nanostructures. Dynamic light scattering (DLS) results identified that the micelles have an average hydrodynamic diameter of 114 nm with a polydispersity index ranging between 0.105 and 0.114. The electrophoretic light scattering (ELS) measurements demonstrated that the micelles have zeta potential values ranging from +38 to +63 mV. It was evident from both ELS and DLS results that the micelles in solution exhibit long-term stability as the samples were able to maintain their size and charge even after a year of storage. Further, the micelles exhibited inherently antibacterial activity against Escherichia coli and furthermore, this antibacterial efficacy was sustained over a period of 1 year. These stable core-crosslinked micelles are proposed to have great potential as antibacterial materials for long-term applications. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48393.     

A Detailed Study of Antibacterial 3‐Acyltetramic Acids and 3‐Acylpiperidine‐2,4‐diones

Inspired by the core fragment of antibacterial natural products such as streptolydigin, 3‐acyltetramic acids and 3‐acylpiperidine‐2,4‐diones have been synthesised from the core heterocycle by direct acylation with the substituted carboxylic acids using a strategy which permits ready access to a structurally diverse compound library. The antibacterial activity of these systems has been established against a panel of Gram‐positive and Gram‐negative bacteria, with activity mostly against the former, which in some cases is very potent. Data consistent with modes of action against undecaprenylpyrophosphate synthase (UPPS) and/or RNA polymerase (RNAP) for a small subset of the library has been obtained. The most active compounds have been shown to exhibit binding at known binding sites of streptolydigin and myxopyronin at UPPS and RNAP. These systems offer potential for their antibacterial activity, and further demonstrate the use of natural products as biologically validated starting points for drug discovery.     

A Simple Fragment of Cyclic Acyldepsipeptides Is Necessary and Sufficient for ClpP Activation and Antibacterial Activity

The development of new antibacterial agents, particularly those with unique biological targets, is essential to keep pace with the inevitable emergence of drug resistance in pathogenic bacteria. We identified the minimal structural component of the cyclic acyldepsipeptide (ADEP) antibiotics that exhibits antibacterial activity. We found that N‐acyldifluorophenylalanine fragments function via the same mechanism of action as ADEPs, as evidenced by the requirement of ClpP for the fragments' antibacterial activity, the ability of fragments to activate Bacillus subtilis ClpP in vitro, and the capacity of an N‐acyldifluorophenylalanine affinity matrix to capture ClpP from B. subtilis cell lysates. N‐acyldifluorophenylalanine fragments are much simpler in structure than the full ADEPs and are also highly amenable to structural diversification. Thus, the stage has been set for the development of non‐peptide activators of ClpP that can be used as antibacterial agents.     

Electrostatic immobilization of cetylpyridinium chloride to poly(vinyl alcohol) hydrogels for the simple fabrication of wound dressings with the suppressed release of antibacterial agents

Polymeric systems for antibacterial wound dressings require chemical reactions or syntheses for attaching or incorporating antibacterial moieties into polymer backbones. However, these materials often fail to satisfy the basic requirements, such as easy and inexpensive synthesis. We speculated that a positively charged organic antibacterial agent would be attracted to the polar groups of poly(vinyl alcohol) (PVA) hydrogels and would show suppressed release. PVA hydrogels containing cetylpyridinium chloride (CPC) were prepared by γ irradiation. CPC was barely released from the hydrogels, probably because of electrostatic interactions, and was stable upon γ irradiation. The suppressed release of CPC conferred antibacterial activity against Escherichia coli to the surface of the hydrogels, whereas no inhibition zone was observed around the hydrogels. The CPC‐containing PVA hydrogels were easy to prepare and contained known and safe materials. The simplicity and safety of this procedure for achieving the suppressed release of antibacterial agents were advantages of these CPC‐containing PVA hydrogels. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40456.     

Synthesis and Evaluation of 3,4‐Dihydropyrimidin‐2(1H)‐ones as Sodium Iodide Symporter Inhibitors

The sodium iodide symporter (NIS) is responsible for the accumulation of iodide in the thyroid gland. This transport process is involved in numerous thyroid dysfunctions and is the basis for human contamination in the case of exposure to radioactive iodine species. 4‐Aryl‐3,4‐dihydropyrimidin‐2(1H)‐ones were recently discovered by high‐throughput screening as the first NIS inhibitors. Described herein are the synthesis and evaluation of 115 derivatives with structural modifications at five key positions on the pyrimidone core. This study provides extensive structure–activity relationships for this new class of inhibitors that will serve as a basis for further development of compounds with in vivo efficacy and adequate pharmacokinetic properties. In addition, the SAR investigation provided a more potent compound, which exhibits an IC₅₀ value of 3.2 nM in a rat thyroid cell line (FRTL5).     

In-situ generation Cu2O/CuO core-shell heterostructure based on copper oxide nanowires with enhanced visible-light photocatalytic antibacterial activity

As visible light-driven photocatalysts in wastewater treatment, Cu₂O/CuO composites have garnered considerable attention. Herein, Cu₂O/CuO core–shell nanowires were fabricated directly on a Cu mesh using a simple two-step synthesis process involving a wet chemical method and rapid annealing. Unlike conventional composite nanowires, controllable core–shell nanowires exhibit high photoelectrochemical properties and overcome the problems associated with the recovery of powder-based photocatalysts. The presence and structural distribution of the Cu₂O/CuO core–shell nanowires were confirmed using X-ray diffraction, X-ray photoelectron spectroscopy and transmission electron microscopy. Among the samples subjected to different rapid annealing temperatures for 180 s, the sample exposed to rapid annealing at 350 °C achieved the highest photocurrent density of ?6.96 mA cm^?2. In the core–shell nanowires fabricated on the samples, the ratio of Cu₂O/CuO was 1:1. The photocatalytic activity of the Cu₂O/CuO nanowire samples was also determined by measuring methyl blue degradation to determine their applicability in wastewater treatment. A remarkable photocatalytic degradation rate of 91.6% was achieved at a loading bias voltage of ?0.5 V. The Cu₂O/CuO heterojunction enhanced the photodegradation of the samples because the different bandgaps improved the dissociation of the photogenerated electron–hole pairs. Furthermore, the antibacterial activity of the Cu₂O/CuO nanowires exhibited considerable resistance against Escherichia coli and photocatalytic antibacterial treatment for only 20 min under visible light killed 10⁶ CFU/mL of E. coli. Therefore, the Cu₂O/CuO controllable core–shell nanowires with a high photodegradation performance and excellent antibacterial activity under general illumination show diverse applications in water treatment.     

An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram-negative Pathogens and Reduced ex vivo Cochleotoxicity

We describe the convergent synthesis of a 5-O-β-D-ribofuranosyl-based apramycin derivative (apralog) that displays significantly improved antibacterial activity over the parent apramycin against wild-type ESKAPE pathogens. In addition, the new apralog retains excellent antibacterial activity in the presence of the only aminoglycoside modifying enzyme (AAC(3)-IV) acting on the parent, without incurring susceptibility to the APH(3’) mechanism that disables other 5-O-β-D-ribofuranosyl 2-deoxystreptamine type aminoglycosides by phosphorylation at the ribose 5-position. Consistent with this antibacterial activity, the new apralog has excellent 30 nM activity (IC₅₀) for the inhibition of protein synthesis by the bacterial ribosome in a cell-free translation assay, while retaining the excellent across-the-board selectivity of the parent for inhibition of bacterial over eukaryotic ribosomes. Overall, these characteristics translate into excellent in vivo efficacy against E. coli in a mouse thigh infection model and reduced ototoxicity vis à vis the parent in mouse cochlear explants.     

Consensus Virtual Screening Identified [1,2,4]Triazolo[1,5-b]isoquinolines As MELK Inhibitor Chemotypes

Maternal Embryonic Leucine-zipper Kinase (MELK) is a current oncotarget involved in a diverse range of human cancers, with the usage of MELK inhibitors being explored clinically. Here, we aimed to discover new MELK inhibitor chemotypes from our in-house compound library with a consensus-based virtual screening workflow, employing three screening concepts. After careful retrospective validation, prospective screening and in vitro enzyme inhibition testing revealed a series of [1,2,4]triazolo[1,5-b]isoquinolines as a new structural class of MELK inhibitors, with the lead compound of the series exhibiting a sub-micromolar inhibitory activity. The structure-activity relationship of the series was explored by testing further analogs based on a structure-guided selection process. Importantly, the present work marks the first disclosure of the synthesis and bioactivity of this class of compounds.     

Antibacterial Activity of Hexadecynoic Acid Isomers toward Clinical Isolates of Multidrug-Resistant Staphylococcus aureus

In the present study, the structural characteristics that impart antibacterial activity to C₁₆ alkynoic fatty acids (aFA) were further investigated. The syntheses of hexadecynoic acids (HDA) containing triple bonds at C-3, C-6, C-8, C-9, C-10, and C-12 were carried out in four steps and with an overall yield of 34–78%. In addition, HDA analogs containing a sulfur atom at either C-4 or C-5 were also prepared in 69–77% overall yields, respectively. Results from this study revealed that the triple bond at C-2 is pivotal for the antibacterial activity displayed by 2-HDA, while the farther the position of the triple bond from the carbonyl group, the lower its bactericidal activity against gram-positive bacteria, including clinical isolates of methicillin-resistant Staphylococcus aureus (CIMRSA) strains. The potential of 2-HDA as an antibacterial agent was also assessed in five CIMRSA strains that were resistant to Ciprofloxacin (Cipro) demonstrating that 2-HDA was the most effective treatment in inhibiting their growth when compared with either Cipro alone or equimolar combinations of Cipro and 2-HDA. Moreover, it was proved that the inhibition of S. aureus DNA gyrase can be linked to the antibacterial activity displayed by 2-HDA. Finally, it was determined that the ability of HDA analogs to form micelles can be linked to their decreased activity against gram-positive bacteria, since critical micellar concentrations (CMC) between 50 and 300 μg/mL were obtained.     

Preparation and properties of transparent,waterproof, and antibacterial composite film materials

Transparent polymer materials, such as plastics, have become widely used in the packaging industry due to their excellent properties. However, their nondegradability has led to a significant environmental issue known as “white pollution.” To address this issue, a transparent antibacterial film material was prepared using carboxymethyl cellulose and carboxymethyl chitosan as raw materials through an acid-assisted freeze–thaw strategy. The material exhibits optical transmittance exceeding 90% and a tensile strength of up to 124.1 MPa. Meanwhile, this material demonstrated excellent waterproof performance as well as antibacterial activity to Staphylococcus aureus and Escherichia coli. Therefore, this film material holds promising potential for development in antibacterial food packaging.     

Nontoxic glasses: Preparation,structural, electrical and biological properties

Bacterial infections affect about 1 in 5 patients who receive a dental implant within 5 years of surgery. To avoid the implant rejection it is necessary for the development of innovative biomaterials, with addition or substitution of the ions, for implant coatings that promote a strong bond with the new host bone and antibacterial action. The objective of this work was to synthesize a bioactive glass with different silver concentrations to evaluate their antibacterial performance. The glasses were synthesized with up to 2% silver content by melt-quenching. Structural, morphological, biological, and electrical properties of all samples were studied. The biological behavior was evaluated through cytotoxicity tests and antibacterial activity. The structural analysis shows that the introduction of silver do not promote significant changes, not altering the advantageous properties of the bioglass of the bioglass. It was verified that the glasses with a silver content from 0.5% to 2%, completely prevented the growth of both Staphylococcus aureus and Escherichia coli while being nontoxic toward mammalian cells. Therefore, these bioglasses are promising materials to be used in the production of dental implants with antimicrobial activity.