Dataset Information

Analysis of the effect of ClpC1 directed antibiotics on ClpC1, ClpC2 and ClpC3 protein levels.

ABSTRACT: Ecumicin and Cyclomarin A (CymA) are known antimicrobial compounds that target the NTD of ClpC1. In proteomics analysis of compound treated M. smegmatis, two novel protein, ClpC2 and ClpC3, have been identified as strong interactors of those compounds in addition to ClpC1. In this study we used PRM to monitor the levels of ClpC1, ClpC2 and ClpC3 over time after treatment with CymA or ecumicin or CymA-based BacPROTACs.

ORGANISM(S): Mycolicibacterium Smegmatis

SUBMITTER: David Hoi

PROVIDER: PXD037198 | panorama | Wed Jun 07 00:00:00 BST 2023

REPOSITORIES: PanoramaPublic

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Publications

Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival.

Hoi David M DM Junker Sabryna S Junk Lukas L Schwechel Kristin K Fischel Katharina K Podlesainski David D Hawkins Paige M E PME van Geelen Lasse L Kaschani Farnusch F Leodolter Julia J Morreale Francesca Ester FE Kleine Stefan S Guha Somraj S Rumpel Klaus K Schmiedel Volker M VM Weinstabl Harald H Meinhart Anton A Payne Richard J RJ Kaiser Markus M Hartl Markus M Boehmelt Guido G Kazmaier Uli U Kalscheuer Rainer R Clausen Tim T

Cell 20230502 10

The ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria. To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism of the antibiotics cyclomarin A and ecumicin. Quantitative proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3. These proteins likely protect the Clp protease from excessive amount ...[more]

PMID: 37137307

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Project description:<p>We have used a "chemistry first" approach to discover druggable acquired vulnerabilities that arised in the pathogenesis of non-small cell lung cancer (NSCLC). We screened chemical libraries (~200,000 compounds) for chemical toxins that killed subsets of NSCLC but not normal human lung epithelial cells (HBECs). We first screened a panel of 12 NSCLC lines that represented a variety of known oncogenotypes and identified chemicals with large Z scores and appropriate properties including re-supply, chemistry, and reproducible drug response phenotypes. This was then narrowed down to a list of 202 chemicals and 18 drugs with known targeting (henceforth called "Precision Oncology Probe Set", or POPS). These, and a panel of 30 clinically available drugs, targeted therapies, and drug combinations, already in use or in trials for NSCLC treatment, were then tested on a panel of 96 NSCLC lines for their drug response phenotypes in 12-point dose response curves. This information was analyzed using scanning ranked KS (Kolmogorov-Smirnov) and elastic net biostatistics approaches to identify molecular biomarkers (mutations, mRNA expression, copy number variation, protein expression, and metabolomics) which could predict for sensitivity or resistance to a particular chemical toxin or treatment regimen. From this we have discovered that: our approach identifies already known molecular biomarker of drug sensitivities (e.g. EGFR mutations and EGFR TK inhibitors); many clinically available chemotherapy agents have molecular biomarkers predicting preclinical model drug responses; the POP set of chemical toxins provides novel drug response phenotype patterns in the large NSCLC panel different from those found with clinically available agents including a therapeutic window; many of the POP toxins only hit a small percentage (~5%) of the NSCLC panel but the POP set as a whole provides "coverage" of the entire NSCLC panel; there are simple, one or 2 component molecular biomarkers (mutations, mRNA expression) that predict responses to the different chemical toxins in the NSCLC panel; and that the molecular biomarkers provide some information on the targets and pathways involved in response to the chemical toxins. Thus, we have identified a group of chemical toxins with selectivity for subsets of NSCLC and associated tumor molecular biomarkers to facilitate their development for precision medicine, and also, in some cases, information on the targets and pathways interdicted by these chemical compounds. In addition, we have discovered NSCLC predictive biomarkers for clinically available agents.</p>

Dataset Information

Analysis of the effect of ClpC1 directed antibiotics on ClpC1, ClpC2 and ClpC3 protein levels.

Publications

Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival.

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