https://libjncir.jncasr.ac.in/xmlui/handle/10572/1487 2026-04-04T05:31:23Z https://libjncir.jncasr.ac.in/xmlui/handle/10572/2493 Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance Yarlagadda, Venkateswarlu; Akkapeddi, Padma; Manjunath, Goutham B.; Haldar, Jayanta The alarming growth of antibiotic resistant superbugs such as vancomycin-resistant Enterococci and Staphylococci has become a major global health hazard. To address this issue, we report the development of lipophilic cationic vancomycin analogues possessing excellent antibacterial activity against several drug-resistant strains. Compared to vancomycin, efficacy greater than 1000-fold was demonstrated against vancomycin-resistant Enterococci (VRE). Significantly, unlike vancomycin, these compounds were shown to be bactericidal at low concentrations and did not induce bacterial resistance. An optimized compound in the series, compared to vancomycin, showed higher activity in methicillin-resistant Staphylococcus aureus (MRSA) infected mouse model and exhibited superior antibacterial activity in whole blood with no observed toxicity. The remarkable activity of these compounds is attributed to the incorporation of a new membrane disruption mechanism into vancomycin and opens up a great opportunity for the development of novel antibiotics. Restricted Access 2014-01-01T00:00:00Z https://libjncir.jncasr.ac.in/xmlui/handle/10572/2491 Effect of amide bonds on the self-assembly of gemini surfactants Hoque, Jiaul; Gonuguntla, Spandhana; Yarlagadda, Venkateswarlu; Aswal, Vinod K.; Haldar, Jayanta This study provides an insight into the micellar aggregation properties in aqueous solutions of various gemini surfactants bearing one or more amide groups at the side chains and/or in the spacer by conductivity and small angle neutron scattering (SANS) studies. The amide functionality was found to enhance the surfactant aggregation properties as compared to the surfactants having no amide bond. Furthermore, the aggregation properties of the gemini surfactants bearing amide groups were found to strongly depend on the position and number of amide bonds. With the increase in the number of amide bonds, the aggregation number (N) and the size of the micelles increased. Additionally, the size and shape of the micelles were also found to depend both on the hydrocarbon chain length and the spacer chain length. It was also found that the aggregation number and the size of the micelles increased with an increase in concentration and decreased with an increase in temperature. The critical micellar concentration (CMC) values of the gemini surfactants obtained by a conductometric method were found to vary greatly with variation in the hydrocarbon chain. Restricted Access 2014-01-01T00:00:00Z https://libjncir.jncasr.ac.in/xmlui/handle/10572/2492 Membrane Active Phenylalanine Conjugated Lipophilic Norspermidine Derivatives with Selective Antibacterial Activity Konai, Mohini M.; Ghosh, Chandradhish; Yarlagadda, Venkateswarlu; Samaddar, Sandip; Haldar, Jayanta Natural and synthetic membrane active antibacterial agents offer hope as potential solutions to the problem of bacterial resistance as the membrane-active nature imparts low propensity for the development of resistance. In this report norspermidine based antibacterial molecules were developed that displayed excellent antibacterial activity against various wild-type bacteria (Gram-positive and Gram-negative) and drug-resistant bacteria (methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and beta-lactam-resistant Klebsiella pneumoniae). In a novel structureactivity relationship study it has been shown how incorporation of an aromatic amino acid drastically improves selective antibacterial activity. Additionally, the effect of stereochemistry on activity, toxicity, and plasma stability has also been studied. These rapidly bactericidal, membrane active antibacterial compounds do not trigger development of resistance in bacteria and hence bear immense potential as therapeutic agents to tackle multidrug resistant bacterial infections. Restricted Access 2014-01-01T00:00:00Z https://libjncir.jncasr.ac.in/xmlui/handle/10572/2300 Isosteric substitution in cationic-amphiphilic polymers reveals an important role for hydrogen bonding in bacterial membrane interactions Uppu, D. S. S. M.; Konai, M. M.; Baul, U.; Singh, P.; Siersma, T. K.; Samaddar, S.; Vemparala, S.; Hamoen, L. W.; Narayana, Chandrabhas; Haldar, Jayanta Biomimetic antibacterial polymers, the functional mimics of antimicrobial peptides (AMPs), targeting the bacterial cell membrane have been developed to combat the problem of antibiotic resistance. Amphiphilicity, a balance of cationic charge and hydrophobicity, in these polymers has been shown to be pivotal for their selective interactions with anionic lipid membranes of bacteria instead of zwitterionic mammalian (human erythrocyte) membranes. However, it is unclear if and to what extent hydrogen bonding in amphiphilic antibacterial polymers contributes to this membrane binding specificity. To address this, we employ isosteric substitution of ester with amide moieties that differ in their potency for hydrogen bonding in the side chains of N-alkyl maleimide based amphiphilic polymers. Our studies reveal that amide polymer (AC3P) is a potent antibacterial agent with high membrane-disrupting properties compared to its ester counterpart (EC3P). To understand these differences we performed bio-physical experiments and molecular dynamics (MD) simulations which showed strong interactions of AC3P including hydrogen bonding with lipid head groups of bacterial model lipid bilayers, that are absent in EC3P, make them selective for bacterial membranes. Mechanistic investigations of these polymers in bacteria revealed specific membrane disruptive activity leading to the delocalization of cell division related proteins. This unprecedented and unique concept provides an understanding of bacterial membrane interactions highlighting the role of hydrogen bonding. Thus, these findings will have significant implications in efficient design of potent membrane-active agents. Open Access 2016-01-01T00:00:00Z