In Vivo Targeting of Escherichia coli with Vancomycin-Arginine

Abstract

The ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to gram-negative bacteria was investigated. Its MIC towards E. coli including β-lactamase expressing Ambler classes A, B, and D was 8-16μg/ml. Addition of 8×MIC V-r to E. coli was acutely bactericidal and associated with a low frequency of resistance (< 2.3×10−10). In vivo, V-r markedly reduced E. coli burden by >7 log10 CFU/g in a thigh muscle model. These data warrant further development of V-r in combatting E. coli, including resistant forms.

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

“…This modification broadened the spectrum of vancomycin to inhibit Gram‐negative bacteria with V‐R and V‐RR displaying MICs against E. coli of 8 and 12 µ m , respectively. In a mouse in vivo infection model, V‐R displayed over a 4 log unit reduction of an E. coli infection at 200 mg/kg, where vancomycin only reduced the infection by 10‐fold at a high dose (1272 mg/kg) (Neville et al., 2021). Vancomycin has also been conjugated to a full‐length CPP composed of eight arginine residues via the free carboxylic acid on vancomycin (V‐r8; Figure 1a) (Antonoplis et al., 2018).…”

Identification and Quantification of Glycans in Whole Cells: Architecture of Microalgal Polysaccharides Described by Solid-State Nuclear Magnetic Resonance

“…Cellular samples can be assessed using in situ solid-state nuclear magnetic resonance (ssNMR), an emerging nondestructive method with atomic to nanoscale resolution complementing X-ray diffraction and electron microscopy techniques . SsNMR has enabled high-resolution characterization of bacterial cells, − plant tissues, , fungal mycelia and cells, − mammalian cells, viral particles, , and recently algal cultures − under MAS conditions.…”

Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains

“…16,17 Notably, this arginine-vancomycin conjugate was demonstrated to successfully reduce bacterial burden >6-log fold compared to vehicle and vancomycin in a murine thigh E. coli infection model. 16 In addition to such covalent approaches to enhance anti-Gram-negative activity, agents capable of potentiating or synergizing with Gram-positive-specific antibiotics also present an attractive option. In this regard, many OM-disrupting cyclic or linear cationic peptides have been reported to sensitize Gramnegative pathogens to anti-Gram-positive antibiotics including vancomycin.…”

“…Notably, these bicyclic constructs are proposed to target the extracellular part of the OM protein BamA, thereby avoiding the need to pass the OM. 28 Given previous reports showing that covalent attachment of siderophores, LPS binding moieties, or positively charged moieties to vancomycin can lead to improved antimicrobial activity against Gram-negative strains, [15][16][17]29,30 we hypothesized that conjugation of vancomycin to the highly positively charged OM disruptor PMEN could sensitize Gram-negative strains. Our interest in exploring vancomycin-PMEN conjugates was further spurred given that OM disruption has also previously been demonstrated to enable anti-Gram-negative activity for vancomycin.…”

“…More recently, the group of Haldar reported a lipophilic cationic vancomycin analogue, VanQAmC 10 , which was shown to be bactericidal against MDR A. baumannii . Another recent vancomycin derivative, developed by the groups of Wender and Cegelski, involves the introduction of an arginine-amide moiety at the vancomycin C-terminus, significantly enhancing activity against E. coli (MIC 8–16 μM) including resistant strains. , Notably, this arginine-vancomycin conjugate was demonstrated to successfully reduce bacterial burden >6-log fold compared to vehicle and vancomycin in a murine thigh E. coli infection model . In addition to such covalent approaches to enhance anti-Gram-negative activity, agents capable of potentiating or synergizing with Gram-positive-specific antibiotics also present an attractive option.…”