The impact of backbone <i>N</i>‐methylation on the structure‐activity relationship of Leu<sub>10</sub>‐teixobactin

Velkov, Tony; Swarbrick, James; Hussein, Maytham; Schneider‐Futschik, Elena K.; Hoyer, Daniel; Li, Jian; Karas, John A.

doi:10.1002/psc.3206

Cited by 9 publications

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“…While the total synthesis of native teixobactin has been achieved, its preparation is difficult due to the need for the appropriate L-allo-End precursor, which is synthetically challenging to obtain in useful quantities (7,20,21). Leu 10 -teixobactin has emerged as an analogue that has activity comparable to that of native teixobactin and is generally accepted as a suitable substitute by researchers in the field (22)(23)(24). The present report presents the first study aimed at elucidating the bacterial killing mechanism(s) of the Leu 10 -teixobactin analogue against the methicillin-resistant S. aureus (MRSA) strain ATCC 700699 using untargeted metabolomics studies.…”

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The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

et al. 2020

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Antibiotics have served humankind through their use in modern medicine as effective treatments for otherwise fatal bacterial infections. Teixobactin is a first member of newly discovered natural antibiotics that was recently identified from a hitherto-unculturable soil bacterium, Eleftheria terrae, and recognized as a potent antibacterial agent against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. The most distinctive characteristic of teixobactin as an effective antibiotic is that teixobactin resistance could not be evolved in a laboratory setting. It is purported that teixobactin’s “resistance-resistant” mechanism of action includes binding to the essential bacterial cell wall synthesis building blocks lipid II and lipid III. In the present study, metabolomics was used to investigate the potential metabolic pathways involved in the mechanisms of antibacterial activity of the synthetic teixobactin analogue Leu10-teixobactin against a MRSA strain, S. aureus ATCC 700699. The metabolomes of S. aureus ATCC 700699 cells 1, 3, and 6 h following treatment with Leu10-teixobactin (0.5 μg/ml, i.e., 0.5× MIC) were compared to those of the untreated controls. Leu10-teixobactin significantly perturbed bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan (lipid I and II) metabolism, and cell wall teichoic acid (lipid III) biosynthesis as early as after 1 h of treatment, reflecting an initial activity on the cell envelope. Concordant with its time-dependent antibacterial killing action, Leu10-teixobactin caused more perturbations in the levels of key intermediates in pathways of amino-sugar and nucleotide-sugar metabolism and their downstream peptidoglycan and teichoic acid biosynthesis at 3 and 6 h. Significant perturbations in arginine metabolism and the interrelated tricarboxylic acid cycle, histidine metabolism, pantothenate, and coenzyme A biosynthesis were also observed at 3 and 6 h. To conclude, this is the first study to provide novel metabolomics mechanistic information, which lends support to the development of teixobactin as an antibacterial drug for the treatment of multidrug-resistant Gram-positive infections. IMPORTANCE Antimicrobial resistance is one of the greatest threats to the global health system. It is imperative that new anti-infective therapeutics be developed against problematic “superbugs.” The cyclic depsipeptide teixobactin holds much promise as a new class of antibiotics for highly resistant Gram-positive pathogens (e.g., methicillin-resistant Staphylococcus aureus [MRSA]). Understanding its molecular mechanism(s) of action could lead to the design of new compounds with a broader activity spectrum. Here, we describe the first metabolomics study to investigate the killing mechanism(s) of teixobactin against MRSA. Our findings revealed that teixobactin significantly disorganized the bacterial cell envelope, as reflected by a profound perturbation in the bacterial membrane lipids and cell wall biosynthesis (peptidoglycan and teichoic acid). Importantly, teixobactin significantly suppressed the main intermediate d-alanyl-d-lactate involved in the mechanism of vancomycin resistance in S. aureus. These novel results help explain the unique mechanism of action of teixobactin and its lack of cross-resistance with vancomycin.

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The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

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“…6C). 37 Each of these convergent strategies enables rapid access to teixobactin analogues since modifications can be incorporated into smaller peptide precursors that are easier to prepare, prior to the fragment condensation.…”

Section: Total Synthesis Of Teixobactin and Analogues Using A Convergent Approachmentioning

confidence: 99%

“…48,52 Cationic replacement is also possible 38,48a,49,53 but not so for O-phosphorylation 36 or L-Asn incorporation. 48a Nmethylation abolishes activity, 37 presumably due to disruption of hydrogen bonding at the dimer interface between L-Ser 3 of one monomer and L-Ser 7 of the other. 46 This article is protected by copyright.…”

Section: L-sermentioning

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Section: L-ilementioning

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“…53 But once again, Parmar et al were able to incorporate L-Ala 2 into L-Leu 10 -teixobactin and maintain antimicrobial activity, by inserting arginine at residues 3 and 4. 49 N-methylation was also found to abolish activity, 37 possibly due to disruption of the supramolecular assembly of teixobactin and/or a conformational change that disrupts N-terminal binding to the pyrophosphate group of lipid II. 46…”

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Synthesis and structure−activity relationships of teixobactin

Karas

Chen

Schneider‐Futschik

et al. 2019

Annals of the New York Academy of Sciences

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Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

Tang

Wang

et al. 2022

Journal of Peptide Science

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Discovering new antibiotics with novel chemical scaffolds and antibacterial mechanisms presents a challenge for medicinal scientists worldwide as the ever‐increasing bacterial resistance poses a serious threat to human health. A new cyclic peptide‐based antibiotic termed teixobactin was discovered from a screen of uncultured soil bacteria through iChip technology in 2015. Teixobactin exhibits excellent antibacterial activity against all the tested gram‐positive pathogens and Mycobacterium tuberculosis, including drug‐resistant strains. Given that teixobactin targets the highly conserved lipid II and lipid III, which induces the simultaneous inhibition of both peptidoglycan and teichoic acid synthesis, the emergence of resistance is considered to be rather difficult. The novel structure, potent antibacterial activity, and highly conservative targets make teixobactin a promising lead compound for further antibiotic development. This review provides a comprehensive treatise on the advances of teixobactin in the areas of discovery processes, antibacterial activity, mechanisms of action, chemical synthesis, and structural optimizations. The synthetic methods for the key building block l‐allo‐End, natural teixobactin, representative teixobactin analogs, as well as the structure–activity relationship studies will be highlighted and discussed in details. Finally, some insights into new trends for the generation of novel teixobactin analogs and tips for future work and directions will be commented.

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The impact of backbone N‐methylation on the structure‐activity relationship of Leu₁₀‐teixobactin

Cited by 9 publications

References 29 publications

The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

Synthesis and structure−activity relationships of teixobactin

Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

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The impact of backbone N‐methylation on the structure‐activity relationship of Leu10‐teixobactin

Cited by 9 publications

References 29 publications

The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study

Synthesis and structure−activity relationships of teixobactin

Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

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The impact of backbone N‐methylation on the structure‐activity relationship of Leu₁₀‐teixobactin