Dataset Information

An antibacterial β-lactone kills Mycobacterium tuberculosis by infiltrating mycolic acid biosynthesis

ABSTRACT: The spread of antibiotic resistance is a major challenge for treatment of Mycobacterium tuberculosis infection. In addition, efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis leading to rapid cell death. Inspired by this mechanism we exploit β-lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β-lactones we found one hit with potent anti-mycobacterial and bactericidal activity. Chemical proteomics using an alkynylated probe identified Pks13 and Ag85 serine hydrolases as major targets. Validation via enzyme assays and customized 13C metabolite profiling showed that both targets are functionally impaired by the β-lactone. Co-administration with front-line antibiotics enhanced the potency against M. tuberculosis by more than 100-fold demonstrating a therapeutic potential of targeting mycomembrane biosynthesis serine hydrolases.

INSTRUMENT(S): LTQ Orbitrap XL

ORGANISM(S): Mycobacterium Smegmatis (strain Atcc 700084 / Mc(2)155) Mycobacterium Tuberculosis H37rv

DISEASE(S): Tuberculosis

SUBMITTER: Nina Bach

LAB HEAD: Prof. Stephan A. Sieber

PROVIDER: PXD007699 | Pride | 2022-01-19

REPOSITORIES: Pride

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Publications

An Antibacterial β-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis.

Lehmann Johannes J Cheng Tan-Yun TY Aggarwal Anup A Park Annie S AS Zeiler Evelyn E Raju Ravikiran M RM Akopian Tatos T Kandror Olga O Sacchettini James C JC Moody D Branch DB Rubin Eric J EJ Sieber Stephan A SA

Angewandte Chemie (International ed. in English) 20171205 1

The spread of antibiotic resistance is a major challenge for the treatment of Mycobacterium tuberculosis infections. In addition, the efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis, leading to rapid cell death. Inspired by this mechanism, we exploited β-lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β-lactones, we found one hit ...[more]

PMID: 29067779

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Project description:The purpose of this experiment was to do investigatge the transcriptional effect of anti-TNF treatment in patients suffering from rheumatoid arthritis. Two series of hybridizations were performed. Each hybridization was done with a technical replicate (the same amount of RNA taken from the same amplified RNA aliquot labeled in two separate reactions and hybridized onto two separate arrays). In the first series of hybridizations RNA exptracted from biopsies taken before treatment was hybridized in a common reference design to enable comparisons between patients. In the second series RNA from biopsies taken after and before treatment were hybridized on the same chip in a direct design to enable investigation of the effect of treatment. 10 patients (8 females and 2 males, median age 54, range 25-69) meeting the American College of Rheumatology (ACR) criteria for RA were recruited for this study. All patients received infliximab (an antibody directed against TNF-alpha) infusions 3mg/kg at week 0 and than after 2 weeks and 6 weeks. Five of these patients were receiving prednisolon and all ten patients were treated with methotrexate to a maximum of 20 mg per week. Synovial biopsies were obtained during arthroscopy from all patients before and after a median of 9 weeks of treatment (with one exception, patient 7 where the second biopsy was obtained during open surgery). Biopsies were taken at the site of inflammation close to cartilage (cc) or not close to cartilage (ncc), defined as less or more than 1.5 cm away from cartilage, respectively. One biopsy was taken before and after treatment from patient 5, 7, 9 and 10. Multiple biopsies were retrieved before and/or after treatment from patient 1, 2, 3, 4, 6 and 7. Due to small amounts of RNA available for patient 9 it was only used in the second series of hybridizations. The average biopsy weight was 22 mg. The ethical committee at the Karolinska Hospital approved all experiments on human cells and tissues. Informed consent was obtained from all study subjects.

Dataset Information

An antibacterial β-lactone kills Mycobacterium tuberculosis by infiltrating mycolic acid biosynthesis

Publications

An Antibacterial β-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis.

Similar Datasets

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