Dimeric Cholic Acid Peptide Conjugates Act as Effective Antibiotic Adjuvants against Multidrug Resistance (MDR) Gram‐Negative Bacterial Infections

Abstract

Macrolides, glycopeptides, lipopeptides, and oxazolidinones class of antibiotics are used only for Gram‐positive bacteria, and are ineffective against Gram‐negative bacteria due to inability of these antibiotics to cross the Gram‐negative bacterial membranes. Here, dimeric cholic acid peptide conjugates as effective adjuvants that allow penetration of erythromycin across Gram‐negative bacteria are presented, making it effective antimicrobial. Here, it is shown that synthesized dimers 2 and 3, having tetramethylene and pentamethylene spacers respectively between cholic acid‐triglycine conjugates, in combination with erythromycin cause synergistic antimicrobial effect against Gram‐negative bacteria. Biochemical studies reveal that dimer 3 causes outer and inner membrane permeabilization by interacting with lipopolysaccharide and displacing Mg2+ ions, thereby allowing the erythromycin to cross bacterial membranes. Dimer 3 in combination with erythromycin can clear the preformed biofilms of E. coli and P. aeruginosa effectively. It is further demonstrated that combination of dimer 3 and erythromycin can clear wound infections of E. coli and P. aeruginosa. Additionally, activities against multidrug resistant clinical strains of E. coli and P. aeruginosa witness that combination of dimer 3 and erythromycin is an ideal combination to mitigate drug‐resistant infections.

Cholic Acid-Derived Gemini Amphiphile Can Eradicate Interkingdom Polymicrobial Biofilms and Wound Infections

“…For the synthesis of C3-derived gemini amphiphiles, we first synthesized methyl esters of LCA (28), DCA (29), and CA (30) using Fischer esterification reaction from the respective bile acids (25−27) (Scheme 1). 31 Furthermore, methyl esters were treated with chloroacetic anhydride to afford compounds 31−33.…”

“…In our earlier efforts, we designed and developed bile acid-derived conjugates that can disrupt microbial membranes and mitigate bacterial and fungal infections. , Moreover, recent studies showed that dimeric amphiphiles displayed unique antibacterial properties , and can target drug-resistant bacteria while maintaining a minimal impact on mammalian cells (Figure ). − Furthermore, dimeric amphiphiles are reported to be immunologically tolerable and have more therapeutic potency than monomeric amphiphiles. Therefore, inspired by these studies, here we present the synthesis and biological evaluation of a series of 24 bile acid-derived gemini amphipathic molecules using lithocholic acid (LCA), deoxycholic acid (DCA), and CA that can target the microbial membranes.…”

Synthesis and Synergistic Antimicrobial Efficacy of Covalent Conjugates Composed of Epsilon-Poly-l-lysine and Beta-Lactam Antibiotics

“…To tackle the challenges posed by MDR microbes, strategies were devised against their resistant types (mainly classified as adaptive, acquired, and intrinsic antimicrobial resistances). 6 These strategies involve prescribing antibiotics of appropriate types and dosages, investigating the mechanisms of horizontal transfer or mutation 7,8 and introducing defect genes into drug-resistance gene sequences. 9 Furthermore, enhancing the antimicrobial effectiveness of current drugs against MDR microbes by employing multiple mechanisms holds practical value.…”