Deciphering the Role of Intramolecular Networking in Cholic Acid–Peptide Conjugates on the Lipopolysaccharide Surface in Combating Gram-Negative Bacterial Infections

Abstract

The presence of lipopolysaccharide and emergence of drug resistance make the treatment of Gramnegative bacterial infections highly challenging. Herein, we present the synthesis and antibacterial activities of cholic acid−peptide conjugates (CAPs), demonstrating that valine− glycine dipeptide-derived CAP 3 is the most effective antimicrobial. Molecular dynamics simulations and structural analysis revealed that a precise intramolecular network of CAP 3 is maintained in the form of evolving edges, suggesting intramolecular connectivity. Further, we found high conformational rigidity in CAP 3 that confers maximum perturbations in bacterial membranes relative to other small molecules. Interestingly, CAP 3-coated catheters did not allow the formation of biofilms in mice, and treatment of wound infections with CAP 3 was able to clear the bacterial infection. Our results demonstrate that molecular conformation and internal connectivity are critical parameters to describe the antimicrobial nature of compounds, and the analysis presented here may serve as a general principle for the design of future antimicrobials.

Exploring structural dynamics and optical properties of UnaG fluorescent protein upon N57 mutations

“…To better understand the individual conformational space of BLR in each system, we also performed clustering analysis of BLR based on its RMSD 44,45 (see Fig. S12, S13 and Table S3, ESI†).…”

Microbial Interkingdom Biofilms and the Quest for Novel Therapeutic Strategies

“…By adapting this molecule to better resemble the amphiphilic and cationic characteristics of AMPs, nonpeptide compounds referred to as "ceragenins" were developed [107]. Subsequently, cholic acid-peptide conjugates (CAPs), in which dipeptide units are conjugated on a cholic acid backbone, were shown to effectively interact with lipopolysaccharides and the valine-glycine dipeptide-derived CAP 3 was shown to be the most effective against Gram-negative bacteria [108]. Recently, CAP 3 was also tested against C. albicans, S. aureus, and polymicrobial biofilms [77].…”

Macromolecular Nanotherapeutics and Antibiotic Adjuvants to Tackle Bacterial and Fungal Infections

“…Researchers throughout the world have developed numerous polymeric architecture including random copolymers, block copolymers, homopolymers, zwitterionic, and branched polymers with different polymeric backbone, such as polynorbornenes/oxanorbornenes ( Figure 2 A), [ 78–84 ] polymethacrylate/polyacrylates (Figure 2B), [ 85–91 ] poly‐ β −lactam (Figure 2C), [ 92–95 ] polymaleimides (Figure 2D), [ 95–100 ] glycosylated cationic block co‐beta‐peptides (Figure 2E), [ 101 ] polycarbonates (Figure 2F), [ 102–107 ] polyamides, [ 108 ] poly(benzyl ether)s, [ 109 ] polyionenes, [ 110,111 ] poly(2‐oxazoline), [ 112,113 ] and many other polymeric amphiphiles (Figure 2). [ 114–130 ] Readers can follow development of antimicrobial polymers which have been extensively covered in several earlier review article. [ 30,32,131–137 ] Herein, we will focus on the development antimicrobial polymers which exert their antimicrobial activity through the formation of nanoaggregates with some prominent experimental evidences.…”