Syntheses of potent teixobactin analogues against methicillin-resistant Staphylococcus aureus (MRSA) through the replacement of l-allo-enduracididine with its isosteres

Abstract

We have synthesised 8 simplified, potent teixobactin analogues by replacing l-allo-enduracididine with its isosteres.

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

“…[24] As imilar result against MRSA ATCC 33591 has recently been observed by Singh and co-workers. [37] However, based on the MIC values, we observed that (Lys 10 )teixobactin was in fact consistently 2-fold less potent compared to (Arg 10 )teixobactin acrosst he S. aureus strainst ested;t he IC 50 data similarly reported a2 .2-fold loss of activity.B ecause (Arg 10 )teixobactin showed ab etter antibacterial profile here, Arg was maintained at this positioni nt he analogues 57-62 in our initial SAR study.…”

“…reported that (Lys 10 )teixobactin showed 2‐ to 4‐fold lower MIC values than (Arg 10 )teixobactin against specific strains of Staphylococcus epidermidis , Streptococcus salivarus , Enterococcus durans and Bacillus subtilis . A similar result against MRSA ATCC 33591 has recently been observed by Singh and co‐workers . However, based on the MIC values, we observed that (Lys 10 )teixobactin was in fact consistently 2‐fold less potent compared to (Arg 10 )teixobactin across the S. aureus strains tested; the IC 50 data similarly reported a 2.2‐fold loss of 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 .…”

“…In lesst han three years since its discovery, more than ah undred analogues have been synthesised by various research groups in the hope of elucidating itsstructure-activity relationships (SARs). [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] The biological activities of these analogues and the different synthetic strategies reported have been comprehensively reviewed. [38,39] 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.…”

In Vitro Antibacterial Activity of Teixobactin Derivatives on Clinically Relevant Bacterial Isolates

“…Teixobactin is an 11-amino acid “head to side-chain” cyclodepsipeptide ( Figure 1 ) with a D-Thr as a bridge head that forms the ester with the carboxylic group of a L-Ile. L-Ala and the post-translational modified L- allo- enduracidine (End), which contains a cyclic guanidine, are also part of the cycle ( Abdel Monaim et al, 2016a ; Dhara et al, 2016 ; Giltrap et al, 2016 ; Jin et al, 2016 , 2017 ; Yang et al, 2016 , 2017 ; Monaim et al, 2017 ; Parmar et al, 2017a , b ; Schumacher et al, 2017 ; Wu et al, 2017 ). The tail is formed by two moieties of L-Ser, two moieties of L-Ile, D- allo- Ile and D-Gln ending with a N- Me-D-Phe.…”