Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding

Abstract

Leu10-teixobactin and Ile10-teixobactin have shown comparable activity to natural teixobactin.

Probing key elements of teixobactin–lipid II interactions in membranes

“…Interestingly, recent discoveries of several highly active Txb analogs22–24 all contain allo -End10 substitutions with medium-sized hydrophobic residues, suggesting that this secondary phosphate coordinating group at the residue 10 position is not absolutely required. Introduction of another d -Arg4 substitution of d -Gln4 in the context of Leu10 substitution of allo -End10, however, further reduces the minimal inhibitory concentrations of the Txb analog 24.…”

“…This means hydrophobic interactions are expected to play significant roles in Txb's activity. Granted, most known Txb analogs with substituted mid-chain hydrophobic residues lose their antimicrobial activities,11,15,16,22 indicating that hydrophobic interactions are indeed essential for Txb–lipid II binding.…”

“…The binding between a potent Txb analog and a soluble lipid II analog has been quantified in aqueous solution using isothermal titration calorimetry, where the apparent affinity constant K d was measured at 23 μM with 2 : 1 stoichiometry 26. Similarly, the apparent K d between another Txb analog and a different soluble lipid II analog was measured at 138 μM using quantitative NMR analysis 22. Both numbers are two to three orders of magnitude higher than the minimal inhibitory concentration of Txb (∼0.25 mg L –1 ,6 or ∼200 nM).…”

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…[144] Further comprehensive studies revealed that the synergistic inhibition of both peptidoglycan and teichoic acid synthesis results in cell-wall damage,d elocalization of autolysins,a nd ultimately cell lysis. [149][150][151] This peptide is readily available synthetically and shows excellent antibacterial activity against MRSA (MIC of 0.125 mgmL À1 )a nd 18 additional Gram-positive strains.I mportantly,t he peptide does not exhibit toxicity, neither in vitro nor in vivo (topical administration in arabbit corneal damage model), and clears infections in amouse-eye model of S. aureus keratitis as well as the approved antibiotic moxifloxacin. [146] Va rious groups have pursued the total synthesis of teixobactin and its corresponding analogues.A dditionally, NMR and crystallographic studies have given insight into the structural details of the peptide and identified the macrolactone ring to be essential for pyrophosphate binding and thus the antibiotic effect (all of this is summarized excellently by Guo et al [147] and Fiers et al [148] ).…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…[144] Der Wirkmechanismus von Te ixobactin wurde mittels makromolekularer Inkorporationsstudien aufgeklärt, die eine starke Inhibition der Peptidoglycanbiosynthese nach Behandlung mit dem Wirkstoff offenbarten. [149][150][151] Dieses Peptid kann durch Standardmethoden synthetisiert werden und besitzt eine ausgezeichnete Aktivitätg egen MRSA (MIC von 0.125 mgmL À1 )u nd 18 weitere Gram-positive Stämme.E sz eigt keinerlei Toxizität in vitro und in vivo.A ußerdem heilt das Peptid durch S. aureus verursachte Keratitis-Infektionen in einem Maus-Augenmodell ähnlich gut wie das zugelassene Antibiotikum Moxifloxacin. Dazu gehçren z.…”