Lipopeptidomimetics derived from teixobactin have potent antibacterial activity against Staphylococcus aureus

Abstract

A series of lipopeptidomimetics derived from teixobactin have been prepared that probe the role of residues (1-6) as a membrane anchor and the function of enduracididine. The most active compounds, with a farnesyl tail and End10 to Lys10 or Orn10 substitution have potent activity (MIC 8 μg mL) against S. aureus. These results pave the way for the synthesis of simple, cost-effective yet potent lipopeptidomimetic antimicrobials.

Structures of teixobactin-producing nonribosomal peptide synthetase condensation and adenylation domains

“…The nonribosomal peptides produced in bacteria are of great interest to the pharmaceutical industry because of their antibacterial, antiviral, and anticancer properties ( Walsh, 2015 , Gulick, 2017 , Agrawal et al, 2017 ). The newly discovered nonribosomal compound teixobactin, produced by an uncultured soil beta-proteobacterium, Eleftheria terrae , represents the first of a new class of antibiotics against Gram-positive organisms ( Ling et al, 2015 , Girt et al, 2018 ) that kills important pathogens, including methicillin resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP), and Mycobacterium tuberculosis without detectable resistance, although it is expected that resistance will eventually develop in clinical settings. Teixobactin also shows some activity against Clostridium difficile , which is known to cause nosocomial diarrhea, and Bacillus anthracis .…”

Thiol-ene Enabled Chemical Synthesis of Truncated S-Lipidated Teixobactin Analogs

“…In light of the fact that End is not essential for antimicrobial activity, many ensuing reports of synthetic analogs used l -Arg 10 -teixobactin as the starting point to conduct structure-activity relationship (SAR) studies of teixobactin (Abdel Monaim et al, 2016 , 2017 , 2018 ; Parmar et al, 2016 , 2017a , b , c , 2018 ; Yang H. et al, 2016 ; Chen et al, 2017 ; Jin et al, 2017 , 2018 ; Schumacher et al, 2017 ; Wu et al, 2017 ; Yang et al, 2017 ; Girt et al, 2018 ; Zong et al, 2018 ) Employing this strategy, the Nowick group (Yang H. et al, 2016 ) demonstrated that the teixobactin macrocycle was an important pharmacophore, as a linear Arg 10 analog was inactive. In the same work, they examined the role of the N -terminal tail by replacing residues 1–5 with a 12-carbon linear alkyl lipid.…”

“…It is understood that the N -terminal tail interacts with the plasma membrane to deliver teixobactin into the vicinity of the binding targets, lipid II, and lipid III, in order to confer antibacterial activity (Yang H. et al, 2016 ). Lipobactin later inspired the work of the Jamieson group (Girt et al, 2018 ), who undertook the synthesis of farnesyl- and geranyl-derived lipopeptidomimetics of teixobactin with residues 1–7 truncated. The most potent of the analogs, Lys 10 -farnesylbactin 4 ( Figure 1 ), elicited activity against both Gram-positive and Gram-negative bacteria with moderate potency.…”

“…Structures of teixobactin 1 and teixobactin analogs; Arg 10 -teixobactin 2, lipobactin 3, and Lys 10 -farnesylbactin 4. Examples of most relevant MICs from the literature are shown above each structure Yang H. et al (2016),Girt et al (2018),Zong et al (2018). The End 10 , Arg 10 and Lys 10 substitutions (red) and the lipid moieties of lipobactin 3 and farnesylbactin 4 (blue) are highlighted.…”

Cysteines and Disulfide-Bridged Macrocyclic Mimics of Teixobactin Analogues and Their Antibacterial Activity Evaluation against Methicillin-Resistant Staphylococcus Aureus (MRSA)

“…Brimble et al have also reported on the synthesis and antibacterial activity of teixobactin analogues by replacing l - allo -enduracididine with isosteres [13]. Furthermore, teixobactin analogues with lipid tails were reported by Jamieson et al [14] and recently we described highly potent teixobactin analogues containing proteogenic amino acids at position 10 and their antibacterial activity in vitro and in vivo [15]. As an alternative strategy, we were interested in exploring cysteines and disulfide-briged macrocyclic mimics of teixobactin analogues.…”