New Found Hope for Antibiotic Discovery: Lipid II Inhibitors

Abstract

Abstract:Research into antibacterial agents has recently gathered pace in light of the disturbing crisis of antimicrobial resistance. Development of modern tools offers opportunity of reviving the fallen era of antibacterial discovery through uncovering novel lead compounds that target vital bacterial cell components, such as lipid II. This paper provides a summary of the role of lipid II as well as an overview and insight into the structural features of macrocyclic peptides that inhibit this bacterial cell wall component. The recent discovery of teixobactin, a new class of lipid II inhibitor has generated substantial research interests. As such, the significant progress that has been achieved towards its development as a promising antibacterial agent is discussed.

Probing key elements of teixobactin–lipid II interactions in membranes

“…The structure and chemical composition of Txb have drawn comparison with a completely unrelated compound,48,52 the peptide-based antibiotic hypeptin 53. Surprisingly, even though the two peptide sequences bear no similarity and little is known about the function and mechanism of hypeptin, the two compounds share several common structural features that might indicate their functional and mechanistic resemblance.…”

“…Finally, both antibiotics have a cluster of hydrophobic residues outside the cyclodepsipeptide ring, and the hydrophobic residues in Txb determine its membrane insertion. Based on the shared features, it was hypothesized that hypeptin also targets lipid II 48,52. If true, investigating the common lipid II interactions shared by Txb and hypeptin may lead to the development of a new class of pyrophosphate caging antibiotics.…”

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

“…X‐ray crystallographic, molecular dynamic and NMR structural studies have also been conducted to construct possible binding models of the native peptide and its analogues . Additionally, in a recent mini‐review, we provided an insight into the structural similarities of teixobactin with other lipid II inhibitors . Together, these resources provide tremendous information that could aid the design of optimised analogues.…”

“…[26,27,40] Additionally,i narecent mini-review, we provideda ni nsighti nto the structural similarities of teixobactin with other lipid II inhibitors. [41] Together,t hese resources provide tremendous information thatc ould aid the design of optimised analogues.…”

Teixobactin: a novel anti-infective agent

“…Although the discovery of teixobactin was hailed as a leap forward for the development of novel antimicrobial agents, its development has been slowed due to technical hurdles [13][14][15][16]. The total synthesis of teixobactin is labor-intensive and low yielding (3.3%), and simplified versions of the compound were hypothesized to streamline production without compromising antimicrobial activity.…”