- Vancomycin Derivative Inactivates Carbapenem-Resistant Acinetobacter baumannii and Induces Autophagy
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Vancomycin is a standard drug for the treatment of multidrug-resistant Gram-positive bacterial infections. Albeit, development of resistance (VRE, VRSA) and its inefficacy against persistent infections is a demerit. It is also intrinsically inactive against Gram-negative bacteria. Herein, we report a vancomycin derivative, VanQAmC10, that addresses these challenges. VanQAmC10 was rapidly bactericidal against carbapenem-resistant A. baumannii (6 log10 CFU/mL reduction in 6 h), disrupted A. baumannii biofilms, and eradicated their stationary phase cells. In MRSA infected macrophages, the compound reduced the bacterial burden by 1.3 log10 CFU/mL while vancomycin exhibited a static effect. Further investigation indicated that the compound, unlike vancomycin, promoted the intracellular degradative mechanism, autophagy, in mammalian cells, which may have contributed to its intracellular activity. The findings of the work provide new perspectives on the field of glycopeptide antibiotics.
- Ammanathan, Veena,Chopra, Sidharth,Ghosh, Chandradhish,Haldar, Jayanta,Kaul, Grace,Manjithaya, Ravi,Samaddar, Sandip,Sarkar, Paramita,Shukla, Manjulika,Yarlagadda, Venkateswarlu
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- ANTIMICROBIAL COMPOUNDS AND USES THEREOF
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The present disclosure relates to compounds of Formula I, II, III or its stereoisomers, polymorphs, solvates, hydrates, intermediates, and pharmaceutically active derivatives thereof. The present disclosure relates to a process of preparing the compounds
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Paragraph 00146; 00150; 00152
(2021/10/11)
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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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- 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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- 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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- Tandem ionic liquid antimicrobial toxicity and asymmetric catalysis study: Carbonyl-ene reactions with trifluoropyruvate
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The asymmetric carbonyl-ene reaction of trifluoropyruvate with five alkenes catalysed by [Pd{(R)-BINAP}](SbF6)2 were carried out in good yields and enantioselectivities (up to 96% yield and 96% ee) in low antimicrobial toxicity C2-substituted imidazolium ionic liquids (ILs). Toxicity data was included in the selection criteria for reaction optimisation after a preliminary IL screen. The Pd(ii) catalyst immobilised in an IL was recycled and reused up to 7 times without decrease of either yield or ee. One IL prepared, which was determined to be of high antimicrobial toxicity was assigned a low priority for future applications.
- Gore, Rohitkumar G.,Truong, Thi-Kim-Thu,Pour, Milan,Myles, Lauren,Connon, Stephen J.,Gathergood, Nicholas
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p. 2727 - 2739
(2013/10/08)
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- Solid phase synthesis of a 1,3,5-trisubstituted pyridinium salt library
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The synthesis of a 1,3,5-trisubstituted pyridinium salt combinatorial array containing two variable groups was accomplished in good yields. This entailed the incorporation of 5-bromonicotinic acid onto the resin, followed by Pd(0) catalyzed Suzuki coupling, then alkylation of the pyridine nitrogen and finally cleavage from the resin. A mix and split scheme was also carried out.
- Lago, M. Amparo,Nguyen, Thomas T.,Bhatnagar, Pradip
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p. 3885 - 3888
(2007/10/03)
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