Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci

Abstract

Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria.

Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

“…According to Galbraith et al, saturated fatty acids with 10 or 12 carbon atoms in chain length in general show the highest antimicrobial efficacy [17]. These findings are in accordance with the results of this study and several studies published previously [18][19][20]. Longer fatty acids were found to form aggregates leading to a reduced antibacterial activity [16].…”

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014–2022

“…This result is in stark contrast with the finding that, when appending a hexaarginine moiety, the best antibiotic activity was seen for compound 16 , modified at the N-terminus. 154 Both 16 and 17 are non-hemolytic and non-toxic toward liver and kidney cells. Moreover, in vivo mice experiments with 16 and 17 revealed that the compounds reside in the liver for several hours and do not primarily distribute to the kidneys, unlike vancomycin, 153 , 154 a behavior which could alleviate the risk of nephrotoxicity in patients with renal impairment.…”

Antibiotic–cell‐penetrating peptide conjugates targeting challenging drug‐resistant and intracellular pathogenic bacteria

“…Muhlberg and coworkers have also explored conjugating triarginine and a fatty acid to various locations on periphery of vancomycin (Figure 2d) (Mühlberg et al., 2020). The most potent vancapticin conjugate, V V ‐R 3 C‐C12, had the peptide and lipid conjugated from the vancosamine handle of vancomycin.…”