Design and Syntheses of Highly Potent Teixobactin Analogues against Staphylococcus aureus, Methicillin-Resistant Staphylococcus aureus (MRSA), and Vancomycin-Resistant Enterococci (VRE) in Vitro and in Vivo

Abstract

The cyclic depsipeptide, teixobactin, kills a number of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium tuberculosis without detectable resistance. To date, teixobactin is the only molecule in its class that has shown in vivo antibacterial efficacy. In this work, we designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activities against Staphylococcus aureus, MRSA, and vancomycin-resistant enterococci (VRE) in vitro. One analogue, d-Arg-Leu-teixobactin, 2, was found to be noncytotoxic in vitro and in vivo. Moreover, topical instillation of peptide 2 in a mouse model of S. aureus keratitis decreased the bacterial bioburden (>99.0% reduction) and corneal edema significantly as compared to untreated mouse corneas. Collectively, our results have established the high therapeutic potential of a teixobactin analogue in attenuating bacterial infections and associated severities in vivo.

The impact of backbone N‐methylation on the structure‐activity relationship of Leu10‐teixobactin

“…aureus) isolates. It was found that the minimum inhibitory concentrations (MICs) were comparable with those from previous reports (Table ) including matching MIC values for S . aureus ATCC29213 (0.5 μg/mL) …”

Probing key elements of teixobactin–lipid II interactions in membranes

“…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. Therefore, we speculate that the role of this d -Arg4 residue is also as a positively charged secondary phosphate-coordinator, presumably one that binds the phosphate group farther away from the cyclodepsipeptide ring.…”

“…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.…”

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

“…[145] Thel ack of resistance development so far is ar esult of the multifacetted MoA, combined with the fact that teixobactin addresses ah ighlyconserved non-protein target. [152] In-depth structureactivity relationship (SAR) studies,e specially aiming to replace the synthetically inconvenient l-allo-enduracididine (l-allo-End) amino acid, led to the identification of various potent derivatives,i ncluding d-Arg 4 -Leu 10 -teixobaction ( Figure 6).…”