- Amide Moieties Modulate the Antimicrobial Activities of Conjugated Oligoelectrolytes against Gram-negative Bacteria
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Cationic conjugated oligoelectrolytes (COEs) are a class of compounds that can be tailored to achieve relevant in vitro antimicrobial properties with relatively low cytotoxicity against mammalian cells. Three distyrylbenzene-based COEs were designed containing amide functional groups on the side chains. Their properties were compared to two representative COEs with only quaternary ammonium groups. The optimal compound, COE2?3C?C3-Apropyl, has an antimicrobial efficacy against Escherichia coli with an MIC=2 μg mL?1, even in the presence of human serum albumin low cytotoxicity (IC50=740 μg mL?1) and minimal hemolytic activity. Moreover, we find that amide groups increase interactions between COEs and a bacterial lipid mimic based on calcein leakage assay and allow COEs to readily permeabilize the cytoplasmic membrane of E. coli. These findings suggest that hydrogen bond forming moieties can be further applied in the molecular design of antimicrobial COEs to further improve their selectivity towards bacteria.
- Bazan, Guillermo C.,Limwongyut, Jakkarin,Moreland, Alex S.,Nie, Chenyao,Read de Alaniz, Javier
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- Alkyl-Aryl-Vancomycins: Multimodal Glycopeptides with Weak Dependence on the Bacterial Metabolic State
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Resistance to last-resort antibiotics such as vancomycin for Gram-positive bacterial infections necessitates the development of new therapeutics. Furthermore, the ability of bacteria to survive antibiotic therapy through formation of biofilms and persiste
- Sarkar, Paramita,Basak, Debajyoti,Mukherjee, Riya,Bandow, Julia E.,Haldar, Jayanta
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p. 10185 - 10202
(2021/07/28)
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- Development of Membrane-Active Honokiol/Magnolol Amphiphiles as Potent Antibacterial Agents against Methicillin-Resistant Staphylococcus aureus (MRSA)
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Currently, infections caused by drug-resistant bacteria have become a new challenge in anti-infective treatment, seriously endangering public health. In our continuous effort to develop new antimicrobials, a series of novel honokiol/magnolol amphiphiles were prepared by mimicking the chemical structures and antibacterial properties of cationic antimicrobial peptides. Among them, compound 5i showed excellent antibacterial activity against Gram-positive bacteria and clinical MRSA isolates (minimum inhibitory concentrations (MICs) = 0.5-2 μg/mL) with low hemolytic and cytotoxic activities and high membrane selectivity. Moreover, 5i exhibited rapid bactericidal properties, low resistance frequency, and good capabilities of disrupting bacterial biofilms. Mechanism studies revealed that 5i destroyed bacterial cell membranes, resulting in bacterial death. Additionally, 5i displayed high biosafety and potent in vivo anti-infective potency in a murine sepsis model. Our study indicates that these honokiol/magnolol amphiphiles shed light on developing novel antibacterial agents, and 5i is a potential antibacterial candidate for combating MRSA infections.
- Bai, Li-Ping,Fu, Xiangjing,Guo, Yong,Han, Meiyue,Hou, Enhua,Liu, Jifeng,Qin, Shangshang,Wen, Tingyu,Yan, Xiaoting
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p. 12903 - 12916
(2021/09/13)
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- Low-toxicity amphiphilic molecules linked by an aromatic nucleus show broad-spectrum antibacterial activity and low drug resistance
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Amphiphilic molecules linked by an aromatic nucleus were developed that showed high selectivity toward bacteria over mammalian cells, and low drug resistance. A promising compound 4g exhibited strong bactericidal activity against a panel of sensitive and resistant bacteria, low toxicity, the ability to reduce cell viability in biofilms, stability in mammalian fluids, rapid killing of pathogens, and high in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA).
- Chu, Wenchao,Yang, Yi,Qin, Shangshang,Cai, Jianfeng,Bai, Mengmeng,Kong, Hongtao,Zhang, En
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supporting information
p. 4307 - 4310
(2019/04/17)
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- Small antibacterial molecules highly active against drug-resistant: Staphylococcus aureus
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The rapid growth of antibiotic resistance in Staphylococcus aureus coupled with their biofilm forming ability has made the infections difficult to treat with conventional antibiotics. This has created a massive threat towards public health and is a huge concern worldwide. Aiming to address this challenging issue, herein we report a new class of small antibacterial molecules (SAMs) with high antibacterial activity against multidrug-resistant S. aureus. The design principle of the molecules was based on the variation of hydrophobic/hydrophilic balance through incorporation of two quaternary ammonium groups, ethanol moieties, non-peptidic amide bonds and aliphatic chains. The lead compound, identified through a comprehensive analysis of structure-activity relationships, displayed high activity against clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) with MIC values in the range of 1-4 μg mL-1. More importantly, this compound was capable of killing stationary phase bacteria and disrupting established biofilms of MRSA. Additionally, the compound revealed minimum toxicity towards human erythrocytes (HC50 = 577 μg mL-1) and did not show significant toxicity towards mammalian cells (MDCK and A549) up to 128 μg mL-1. Remarkably, the incorporation of non-peptidic amide bonds made the compounds less susceptible to degradation in human plasma, serum and mouse liver homogenate. Taken together, the results therefore indicate great promise for this class of molecules to be developed as potent antibacterial agents in treating infections caused by drug-resistant S. aureus.
- Dey, Rajib,De, Kathakali,Mukherjee, Riya,Ghosh, Sreyan,Haldar, Jayanta
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supporting information
p. 1907 - 1915
(2019/11/20)
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- Amide aromatic phenol antibacterial peptide analogue with antibacterial activity and preparation method thereof
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The invention belongs to the technical field of pharmaceutical chemistry, and discloses an amide aromatic phenol antibacterial peptide analogue with drug-resistance bacteria resistant activity and without obvious toxicity and a preparation method thereof. The target product is obtained by 3-4 reaction steps, and the main structure of the product is shown as follows. In-vitro antibacterial activityexperiments prove that most of the series of compounds have excellent activity on Gram-positive staphylococcus aureus and enterococcus faecalis, Gram-negative Escherichia coli and stenotrophomonas maltophilia, and the compounds have excellent broad spectrum antibacterial activity; moreover, in-vitro red cell hemolytic data is low in toxicity and has excellent selectivity. One part of the compounds also have excellent antibacterial activity on 'superbacteria' comprising drug-resistant methicillin staphylococcus aureus (MRSA), clinical strains producing enzymes NDM-1 and KPC-2 and the like. Therefore, the series of compounds are expected to serve as novel antibacterial candidate drugs.
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Paragraph 0085; 0086; 0090
(2018/12/03)
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- Antibacterial and Antibiofilm Activity of Cationic Small Molecules with Spatial Positioning of Hydrophobicity: An in Vitro and in Vivo Evaluation
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More than 80% of the bacterial infections are associated with biofilm formation. To combat infections, amphiphilic small molecules have been developed as promising antibiofilm agents. However, cytotoxicity of such molecules still remains a major problem. Herein we demonstrate a concept in which antibacterial versus cytotoxic activities of cationic small molecules are tuned by spatial positioning of hydrophobic moieties while keeping positive charges constant. Compared to the molecules with more pendent hydrophobicity from positive centers (MIC = 1-4 μg/mL and HC50 = 60-65 μg/mL), molecules with more confined hydrophobicity between two centers show similar antibacterial activity but significantly less toxicity toward human erythrocytes (MIC = 1-4 μg/mL and HC50 = 805-1242 μg/mL). Notably, the optimized molecule is shown to be nontoxic toward human cells (HEK 293) at a concentration at which it eradicates established bacterial biofilms. The molecule is also shown to eradicate preformed bacterial biofilm in vivo in a murine model of superficial skin infection.
- Hoque, Jiaul,Konai, Mohini M.,Sequeira, Shanola S.,Samaddar, Sandip,Haldar, Jayanta
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p. 10750 - 10762
(2016/12/16)
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- Membrane Active Small Molecules Show Selective Broad Spectrum Antibacterial Activity with No Detectable Resistance and Eradicate Biofilms
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Treating bacterial biofilms with conventional antibiotics is limited due to ineffectiveness of the drugs and higher propensity to develop bacterial resistance. Development of new classes of antibacterial therapeutics with alternative mechanisms of action has become imperative. Herein, we report the design, synthesis, and biological evaluations of novel membrane-active small molecules featuring two positive charges, four nonpeptidic amide groups, and variable hydrophobic/hydrophilic (amphiphilic) character. The biocides synthesized via a facile methodology not only displayed good antibacterial activity against wild-type bacteria but also showed high activity against various drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and β-lactam-resistant Klebsiella pneumoniae. Further, these biocides not only inhibited the formation of biofilms but also disrupted the established S. aureus and E. coli biofilms. The membrane-active biocides hindered the propensity to develop bacterial resistance. Moreover, the biocides showed negligible toxicity against mammalian cells and thus bear potential to be used as therapeutic agents.
- Hoque, Jiaul,Konai, Mohini M.,Gonuguntla, Spandhana,Manjunath, Goutham B.,Samaddar, Sandip,Yarlagadda, Venkateswarlu,Haldar, Jayanta
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p. 5486 - 5500
(2015/08/03)
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- Effect of lanthanide complex structure on cell viability and association
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A systematic study of the effect of hydrophobicity and charge on the cell viability and cell association of lanthanide metal complexes is presented. The terbium luminescent probes feature a macrocyclic polyaminocarboxylate ligand (DOTA) in which the hydrophobicity of the antenna and that of the carboxyamide pendant arms are independently varied. Three sensitizing antennas were investigated in terms of their function in vitro: 2-methoxyisophthalamide (IAM(OMe)), 2-hydroxyisophthalamide (IAM), and 6-methylphenanthridine (Phen). Of these complexes, Tb-DOTA-IAM exhibited the highest quantum yield, although the higher cell viability and more facile synthesis of the structurally related Tb-DOTA-IAM(OMe) platform renders it more attractive. Further modification of this latter core structure with carboxyamide arms featuring hydrophobic benzyl, hexyl, and trifluoro groups as well as hydrophilic amino acid based moieties generated a family of complexes that exhibit high cell viability (ED 50 > 300 μM) regardless of the lipophilicity or the overall complex charge. Only the hexyl-substituted complex reduced cell viability to 60% in the presence of 100 μM complex. Additionally, cellular association was investigated by ICP-MS and fluorescence microscopy. Surprisingly, the hydrophobic moieties did not increase cell association in comparison to the hydrophilic amino acid derivatives. It is thus postulated that the hydrophilic nature of the 2-methoxyisophthalamide antenna (IAM(OMe)) disfavors the cellular association of these complexes. As such, responsive luminescent probes based on this scaffold would be appropriate for the detection of extracellular species.
- Peterson, Katie L.,Dang, Jonathan V.,Weitz, Evan A.,Lewandowski, Cutler,Pierre, Valerie C.
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supporting information
p. 6013 - 6021
(2014/07/07)
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