Lysine Scanning of Arg₁₀–Teixobactin: Deciphering the Role of Hydrophobic and Hydrophilic Residues

Abstract

Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against Gram positive bacteria. Taking Arg10–teixobactin as a reference, where the nonproteinogenic residue l-allo-enduracididine was substituted by arginine, a lysine scan was performed to identify the importance of keeping the balance between hydrophilic and hydrophobic amino acids for the antimicrobial activities of this peptide family. Thus, the substitution of four isoleucine residues present in the natural sequence by lysine led to a total loss of activity. On the other hand, the substitution of the polar noncharged residues and alanine by lysine allowed us to keep and in some cases to improve the antimicrobial activity.

Rational Design and Synthesis of Modified Teixobactin Analogues: In Vitro Antibacterial Activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa

“…This indicates that a minimum of four carbon atoms is necessary for optimal hydrophobic interactions. The importance of a non‐polar group at position 11 was also evident in previous studies, which showed that the substitution of Ile with a polar residue, such as Lys, abolished the antibacterial activity …”

“…Teixobactin ( 1 ), comprised of a 13‐membered depsipeptide core and a tethered linear heptapeptide, offers multiple sites for synthetic modifications to improve its potency and efficacy. In less than three years since its discovery, more than a hundred analogues have been synthesised by various research groups in the hope of elucidating its structure–activity relationships (SARs) . The biological activities of these analogues and the different synthetic strategies reported have been comprehensively reviewed .…”

Probing key elements of teixobactin–lipid II interactions in membranes

“…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.…”

Dissecting the Binding Interactions of Teixobactin with the Bacterial Cell‐Wall Precursor Lipid II

“…The Gram‐negative lipid II binding of the other two analogues investigated (with Ser to Lys substitution at position 3 or d ‐Gln to d ‐Lys at position 4 of the linear tail of teixobactin) was approximately 100‐fold weaker, with dissociation constants of 63 and 38 μ m for analogues 4 and 5 , respectively. These analogues were designed with the results from the Albericio group in mind, which showed that positions 3 and 4 Lys substitutions are tolerated and activity is largely maintained …”