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

Parmar, Anish; Iyer, Abhishek; Lloyd, Daniel G.; Vincent, Charlotte S.; Prior, Stephen H.; Madder, Annemieke; Taylor, Edward J.; Singh, Ishwar

doi:10.1039/c7cc04021k

Cited by 32 publications

(41 citation statements)

References 13 publications

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“…[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.…”

Section: Broth Microdilution and Growth Inhibition Assaysmentioning

confidence: 70%

“…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.…”

Section: Resultsmentioning

confidence: 93%

“…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 .…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Kuehne

Chan

2018

Chemistry A European J

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Teixobactin, a recently discovered depsipeptide that binds to bacterial lipid II and lipid III, provides a promising molecular scaffold for the design of new antimicrobials. Herein, we describe the synthesis and antimicrobial evaluation of systematically modified teixobactin analogues. The replacement of the Ile residue with aliphatic isosteres, the modification of the guanidino group at residue 10 and the introduction of a rigidifying residue, that is, dehydroamino acid, into the macrocyclic ring generated useful structure-activity information. Extensive antimicrobial susceptibility assessment against a panel of clinically relevant Staphylococcus aureus and Propionibacterium acnes strains led to the identification of the new lead compound, [Arg(Me) ,Nle ]teixobactin, with an excellent bactericidal activity (minimum inhibitory concentration (MIC)=2-4 μg mL ). Significantly, the antimicrobial activity of several of the teixobactin analogues against the pathogenic Gram-negative Pseudomonas aeruginosa was "restored" when combined with the sub-MIC concentration of the outer membrane-disruptive antibiotic colistin. The antimicrobial effectiveness of a [Tfn ,Nle ]teixobactin (32 μg mL )-colistin (2 μg mL ; 0.5×MIC) combination against P. aeruginosa PAO1 reveals, for the first time, an alternative therapeutic option in the treatment of Gram-negative infections.

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Section: Broth Microdilution and Growth Inhibition Assaysmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Kuehne

Chan

2018

Chemistry A European J

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) are included on the WHO high priority list of pathogens that require urgent intervention. Hence emphasis needs to be placed on developing novel class of molecules to tackle these pathogens. Teixobactin is a new class of antibiotic that has demonstrated antimicrobial activity against common bacteria. Here we examined the antimicrobial properties of three Teixobactin derivatives against clinically relevant bacterial isolates taken from South African patients. The minimum inhibitory concentration (MIC), the minimal bactericidal concentration (MBC), the effect of serum on MICs and the time-kill kinetics studies of our synthesized Teixobactin derivatives (3, 4, and 5) were ascertained following the CLSI 2017 guidelines and using the broth microdilution method. Haemolysis on red blood cells (RBCs) and cytotoxicity on peripheral blood mononuclear cells (PBMCs) were performed to determine the safety of these compounds. The MICs of 3, 4, and 5 against reference strains were 4–64 μg/ml, 2–64 μg/ml, and 0.5–64 μg/ml, respectively. The MICs observed for MRSA were (3) 32 μg/ml, (4) 2–4 μg/ml and (5) 2–4 μg/ml whilst those for VRE were (3) 8–16 μg/ml, (4) 4 μg/ml and (5) 2–16 μg/ml, respectively. In the presence of 50% human serum, there was no significant effect on the MICs. The compounds did not exhibit any effect on cell viability at their effective concentrations. Teixobactin derivatives (3, 4, and 5) inhibited bacterial growth in drug-resistant bacteria and hence emerge as potential antimicrobial agents. Molecular dynamic simulations suggested that the most dominant binding mode of Lys10-teixobactin (4) to lipid II is through the amide protons of the cycle, which is identical to data described in the literature for the natural teixobactin hence predicting the possibility of a similar mechanism of action.

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Chemistry and Biology of Teixobactin

Guo

Mandalapu

et al. 2017

Chemistry A European J

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Bacterial resistance to existing drugs is becoming a serious public health issue, urging extensive search for new antibiotics. Teixobactin, a cyclic depsipeptide discovered in a screen of uncultured bacteria, shows potent activity against all the tested Gram-positive bacteria. Remarkably, no teixobactin-resistant bacterial strain has been obtained despite extensive efforts, highlighting the great potential of teixobactin as a lead compound in the fight against antimicrobial resistance (AMR). This review summarizes recent progresses in the understanding of many aspects of teixobactin, including chemical structure, biological activity, biosynthetic pathway, and mode of action. We also discuss the different synthetic strategies in producing teixobactin and its analogues, and the structure-activity relationship (SAR) studies.

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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.

Cited by 32 publications

References 13 publications

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

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

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

Chemistry and Biology of Teixobactin

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