Teixobactin and Its Analogues: A New Hope in Antibiotic Discovery

Abstract

Increasing bacterial resistance against current antibiotics and lack of new molecules to combat bacterial resistance are key challenges to global health. There is, therefore, a continuing need to develop new antibiotics. Teixobactin, a cyclic undecapeptide, displays excellent antibacterial activities against a range of pathogenic bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. Interestingly, it operates by multiple modes of actions and is bactericidal toward S. aureus without detectable resistance. This unique combination of wide Gram-positive activity coupled with its inability to elicit resistance make teixobactin a very attractive molecule for antimicrobial therapeutic development. This Viewpoint discusses teixobactin, its analogues, and the challenges and opportunities associated with their future development.

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

“…Subsequent in vitro analyses revealed that teixobactin binds to the highly conserved pyrophosphate motifs of multiple bacterial cell-wall substrates,for example,lipid II, aprecursor of peptidoglycan, and lipid III, ap recursor of cell-wall teichoic acid. [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] ). [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.…”

“…[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. [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] ). 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).…”

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

“…Zudem schlugen alle bisherigen Bemühungen, Te ixobactin-resistente Mutanten von S. aureus und M. tuberculosis im Labor zu erzeugen, fehl, was die potentielle Anwendung als therapeutisches Agens bestärkt. [148] Umfangreiche Studien zu Struktur-Wirkungs-Beziehungen (SARs) versuchten insbesondere die präparativ schwer zugängliche Aminosäure l-allo-Enduracididin (l-allo-End) zu ersetzen. Anschließende Invitro-Analysen zeigten, dass Te ixobactin an das hochkonservierte Pyrophosphat-Motivv erschiedener bakterieller Zellwandsubstrate bindet.…”

“…[147] und Fiers et al zusammengefasst. [148] Umfangreiche Studien zu Struktur-Wirkungs-Beziehungen (SARs) versuchten insbesondere die präparativ schwer zugängliche Aminosäure l-allo-Enduracididin (l-allo-End) zu ersetzen. Dadurch konnten verschiedene potente Derivate erhalten werden, wie d-Arg 4 -Leu 10 -Teixobaction (Abbildung 6).…”

Affinity capillary electrophoresis employed for determination of stability constants of antamanide complexes with univalent and divalent cations in methanol

“…Octreotide is synthetic analogue of somatostatin consisting of eight AARs; it causes constriction of splanchnic blood vessels and this way reduces the portal pressure and gastric mucosal blood flow as well. The cyclic peptide antibiotics are, e.g., vancomycin, teixobactin, and daptomycin. Vancomycin is a glycopeptide antibiotic, teixobactin is a peptide‐like secondary metabolite, and daptomycin is a lipopeptide antibiotic.…”