Biomedical subjects

Rajalakshmi Balakrishna

Publications and source records attributed to Rajalakshmi Balakrishna.

4 recordsLinked to original sources

PubMed2006

Structural correlation between lipophilicity and lipopolysaccharide-sequestering activity in spermine-sulfonamide analogs.

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize this complex carbohydrate. A series of aryl and aliphatic spermine-sulfonamide analogs were synthesized and tested in a series of binding and cell-based assays in order to probe the effect of lipophilicity on sequestration ability. A strong correlation was indeed found, supporting the hypothesis that endotoxin-neutralizing ability involves a lipophilic or membrane attachment event. The research discussed herein may be useful for the design of additional carbohydrate recognizing molecules and endotoxin-neutralizing drugs.

Carbohydrate Conformation↗

PubMed2006

Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds.

We have shown that lipopolyamines bind to the lipid A moiety of lipopolysaccharide, a constituent of Gram-negative bacterial membranes, and neutralize its toxicity in animal models of endotoxic shock. In an effort to identify non-polyamine scaffolds with similar endotoxin-recognizing features, we had observed an unusually high frequency of hits containing guanylhydrazone scaffolds in high-throughput screens. We now describe the syntheses and preliminary structure-activity relationships in a homologous series of bis-guanylhydrazone compounds decorated with hydrophobic functionalities. These first-generation compounds bind and neutralize lipopolysaccharide with a potency comparable to that of polymyxin B, a peptide antibiotic known to sequester LPS.

Animals↗

PubMed2006

Structural correlates of antibacterial and membrane-permeabilizing activities in acylpolyamines.

A homologous series of mono- and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gram-negative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C8 or C9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.

Animals↗

PubMed2006

Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses.

A synthetic reexamination of a series of ketodihydronicotinic acid class antibacterial agents was undertaken in an attempt to improve their therapeutic potential. A convenient new synthesis was developed involving hetero Diels-Alder chemistry producing 74 new analogs in a multiple parallel synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4-dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the disappointing activity against bacteria that some of the analogs exhibited.

Anti-Infective Agents↗