Structure-Activity Relationships of Antimicrobial and Lipoteichoic Acid-Sequestering Properties in Polyamine Sulfonamides

Abstract

We have recently confirmed that lipoteichoic acid (LTA), a major constituent of the gram-positive bacterial surface, is the endotoxin of gram-positive bacteria that induces proinflammatory molecules in a Toll-like receptor 2 (TLR2)-dependent manner. LTA is an anionic amphipath whose physicochemical properties are similar to those of lipopolysaccharide (LPS), which is found on the outer leaflet of the outer membranes of gram-negative organisms. Hypothesizing that compounds that sequester LPS could also bind to and inhibit LTA-induced cellular activation, we screened congeneric series of polyamine sulfonamides which we had previously shown effectively neutralized LPS both in vitro and in animal models of endotoxemia. We observed that these compounds do bind to and neutralize LTA, as reflected by the inhibition of TLR2-mediated NF-B induction in reporter gene assays. Structure-activity studies showed a clear dependence of the acyl chain length on activity against LTA in compounds with spermine and homospermine scaffolds. We then sought to examine possible correlations between the neutralizing potency toward LTA and antimicrobial activity in Staphylococcus aureus. A linear relationship between LTA sequestration activity and antimicrobial activity for compounds with a spermine backbone was observed, while all compounds with a homospermine backbone were equally active against S. aureus, regardless of their neutralizing potency toward LTA. These results suggest that the number of protonatable charges is a key determinant of the activity toward the membranes of gram-positive bacteria. The development of resistance to membrane-active antibiotics has been relatively slower than that to conventional antibiotics, and it is possible that compounds such as the acylpolyamines may be useful clinically, provided that they have an acceptable safety profile and margin of safety. A more detailed understanding of the mechanisms of interactions of these compounds with LPS and LTA, as well as the gram-negative and -positive bacterial cell surfaces, will be instructive and should allow the rational design of analogues which combine antisepsis and antibacterial properties.Sepsis and its sequel, septic shock, a consequence of systemic inflammation that leads to multiple-organ failure (32

Lipoprotein Lipase and Hydrofluoric Acid Deactivate Both Bacterial Lipoproteins and Lipoteichoic Acids, but Platelet-Activating Factor-Acetylhydrolase Degrades Only Lipoteichoic Acids

“…For instance, antibodies to LTA are currently being investigated as a basis for the treatment of infections with Grϩ bacteria (61). Others have proposed sulfonylamide compounds as therapeutic agents, since sulfonylamide may selectively inactivate LTA without inactivating lipoproteins (59). These new approaches may be less fruitful if LTA is not critically involved in infections with Grϩ bacteria.…”

Bacterial Cell Wall Compounds as Promising Targets of Antimicrobial Agents I. Antimicrobial Peptides and Lipopolyamines

“…We observed that these compounds indeed bind and neutralize LTA, as reflected by the inhibition of TLR2-mediated NF-κB induction in reporter gene assays. Structure-activity studies showed a clear dependence of the acyl chain length on activity against LTA in compounds with spermine and homospermine scaffolds [54]. We then sought to examine possible correlations between the neutralizing potency toward LTA and antimicrobial activity in S. aureus.…”

Monomer spectroscopic analysis and dimer interaction energies on N-(4-methoxybenzoyl)-2-methylbenzenesulfonamide by experimental and theoretical approaches

“…Many sulfa drugs containing SO 2 NH moiety assume an active role in chemotherapeutic field such as sulfonamides, sulphathiazole and sulphamerazine [1][2][3][4].…”