N-terminal aromatic tag induced self assembly of tryptophan–arginine rich ultra short sequences and their potent antibacterial activity

Abstract

Multiple drug resistant (MDR) Staphylococcus aureus is among the most dreaded pathogens for human health in community as well as nosocomial environments. Here we report self assembling ultra short N-terminal modified peptidomimetics based on a template X-W3R4 (where, X = aromatic organic moiety) that show potent activity against multiple MDR S. aureus strains. The active sequences self assemble in water to form nano vesicle (140-190 nm diameter) with positive surface zeta potential and hydrophobic core of Trp residues/N-terminal tags. Further, lethal membrane depolarisation of MRSA cells and a concentration dependent leakage of calcein dye from artificial bacterial mimic membranes established membrane disruptive mode of action for designed sequences. We demonstarte role of N-terminal tag on nature of self assembly and envisage the origin of antibacterial activity to be conformationally aligned nanovesicles which upon interaction lead to disruption of bacterial cells. The designed cell selective nanovesicles may further be exploited towards in vivo applications as antibacterial agent alone or as vehicles for systemic anti-infective therapy. Fig. 3: CD spectra of designed sequences in different environments; water ( ), phosphate buffer ( ) and 50% TFE (v/v) ( ). In (a) Sequence 4, (b) sequence 5, (c) sequence 6 and (d) sequence 7. The spectrum was acquired at a sample concentration of 20 µg/mL. Fig. 4: Trptophan fluorescence spectra of designed sequences in different environments; water ( ), 10 mM Tris buffer ( ) DOPC ( ) DOPC/DOPG ( ) and DMSO ( ). In (a) Sequence 4, (b) sequence 5, (c) sequence 6 and (d) sequence 7. The spectrum was acquired at a sample concentration of 5 µg/mL.

The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

“…GUVs have been employed to investigate the modes of action of several membrane-active antibacterial agents, including daptomycin (38,(42)(43)(44)(45). To mimic the negatively charged S. aureus membrane, we created GUVs consisting of a dioleoyl-sn-glycero-3-phosphocholine (DOPC)/1,2-dioleoyl-sn-glycero-3phospho-(1=-rac-glycerol) (DOPG) lipid bilayer at a ratio of 7:3, which have been used for monitoring the effects of daptomycin and other membrane-active antimicrobial agents on S. aureus lipid bilayers (38,(46)(47)(48)(49). When GUVs were treated with 4 g/ml (1ϫ MIC) PQ401, we noted the formation of lipid aggregates on the surface of the GUVs after ϳ45 s, followed by rupture at ϳ100 s ( Fig.…”

“…The topologies and parameters of the compounds were generated by Automated Topology Builder (54,55). The bacterial membrane was represented by a mixed lipid bilayer composed of 88 neutrally charged DOPC and 40 negatively charged DOPG lipids (ϳ7:3 ratio) with Berger's lipid force field (91), which has been extensively used in previous studies (38,(46)(47)(48). Similarly to our previous studies (6,20,21), water was represented by the SPC/E model (92); a geometric combining rule was adopted for nonbonded interactions of the compounds with lipids, ions, and water (93,94); the fast smooth particle-mesh Ewald method (95) was used to calculate the long-rang electrostatic interactions; and sodium ions were added to neutralize the system.…”

Toward hemocompatible self-assembling antimicrobial nanofibers: understanding the synergistic effect of supramolecular structure and PEGylation on hemocompatibility

“…Recently, several cationic synthetic polymers and peptides have been designed and used as the molecular building blocks to form supramolecular assemblies with tunable, nanostructure-dependent antimicrobial activity. 12, 15, 18, 21, 22 …”

Cell‐penetrating peptide conjugates of indole‐3‐acetic acid‐based DNA primase/Gyrase inhibitors as potent anti‐tubercular agents against planktonic and biofilm culture of Mycobacterium smegmatis

“…TAT peptides have been reported as cell-penetrating peptide known to be used for enhancement of cellular entry and targeting of the drugs and biomolecules (Deshayes et al, 2005). Previously, N-terminal tagging of peptides with different aromatic and aliphatic acids was employed for the enhancement of the potency of several molecules which have shown moderately antibacterial activity against the targeted pathogens (Bisht et al, 2007;Joshi et al, 2015;Laverty et al, 2010). Apart from the cell-penetrating efficiency of the TAT peptide, it was also reported to exhibit the antimicrobial activity against bacteria, fungi, and Mtb strains (Bhosle et al, 2018;Long Zhu & Shin, 2009;Wang et al, 2010).…”