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The killing mechanism of teixobactin against methicillin-resistant Staphylococcus aureus (MRSA): An untargeted metabolomics study

ABSTRACT:

The discovery of antibiotics has led to the effective treatment of bacterial infections that were otherwise fatal and has had a transformative effect on modern medicine. Teixobactin is an unusual depsipeptide natural product that was recently discovered from a previously unculturable soil bacterium which is active against several Gram-positive pathogens, including methicillin- resistant Staphylococcus aureus and vancomycin-resistant Enterococci. One of the key attractive features of teixobactin as an antibiotic lead is that resistance could not be generated in a laboratory setting against S. aureus. This is proposed to be a result of the mechanism of action that involves binding to 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 and mode of action involved in mechanisms of antibacterial activity and bacterial killing of the synthetic teixobactin analog Leu10-teixobactin against an MRSA strain, S. aureus ATCC700699. The metabolomes of S. aureus ATCC700699 cells were compared at 1, 3 and 6 h following treatment with Leu10-teixobactin (0.5 µg/ml, i.e. 0.5x MIC) and 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 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 to support the development of teixobactin as an antibacterial drug for the treatment of multi-drug resistant Gram-positive infections.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

SUBMITTER: Maytham Hussein

PROVIDER: MTBLS1569 | MetaboLights | 2020-04-30

REPOSITORIES: MetaboLights

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Project description:Subinhibitory concentrations of the neuroleptic drug thioridazine (TDZ) are well-known to enhance the killing of methicillin-resistant S. aureus (MRSA) by Î²-lactam antibiotics, however, the mechanism underlying the synergy between TDZ and Î²-lactams is not fully understood. In the present study we have examined the effect of a subinhibitory concentration of TDZ on antimicrobial resistance, the global transcriptome, and the cell wall composition of MRSA USA300. We show that TDZ is able to sensitize the bacteria to several classes of antimicrobials targeting the late stages of peptidoglycan synthesis. Furthermore, our microarray analysis demonstrates that TDZ modulates the expression of genes encoding membrane and surface proteins, transporters, and enzymes involved in amino acid biosynthesis. Interestingly, resemblance between the transcriptional profile of TDZ treatment and the transcriptomic response of S. aureus to known inhibitors of cell wall synthesis suggests that TDZ disturbs peptidoglycan biosynthesis at a stage that precedes transpeptidation. In support of this notion, dramatic changes in the muropeptide profile of USA300 were observed following growth in the presence of TDZ, indicating that TDZ can interfere with the formation of the pentaglycine branches. Strikingly, the addition of glycine to the growth medium relieved the effect of TDZ on the muropeptide profile. Furthermore, exogenous glycine offered a modest protective effect against TDZ-induced Î²-lactam sensitivity. We propose that TDZ exposure leads to a shortage of intracellular amino acids, including glycine, which is required for the production of normal peptidoglycan precursors with pentaglycine branches, the correct substrate of S. aureus penicillin-binding proteins. Collectively, this work demonstrates that TDZ has a major impact on the cell wall biosynthesis pathway in S. aureus and provides new insights into how MRSA may be sensitized towards Î²-lactam antibiotics. Staphylococcus aureus USA300 was grown to early exponential phase and treated with TDZ (16 Âµg/ml) alone or in combination with DCX (0.125 Âµg/ml) for 30 min. Changes in global gene expression were analyzed using the untreated culture as control. Hybridizations were performed in triplicate using RNA isolated from independent cultures.

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The killing mechanism of teixobactin against methicillin-resistant Staphylococcus aureus (MRSA): An untargeted metabolomics study

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