Ein antibakterielles β‐Lacton bekämpft <i>Mycobacterium tuberculosis</i> durch Infiltration der Mykolsäurebiosynthese

Lehmann, Johannes; Cheng, Tan-Yun; Aggarwal, Anup; Park, Annie S.; Zeiler, Evelyn; Raju, Ravikiran M.; Akopian, Tatos; Kandror, Olga; Sacchettini, James C.; Moody, D. Branch; Rubín, Eric J.; Sieber, Stephan A.

doi:10.1002/ange.201709365

Cited by 5 publications

(14 citation statements)

References 37 publications

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“…Various structural modifications based on the Orlistat pharmacophore have been further investigated in order to improve the specificity and antibacterial potency of the new synthesized analogs (Scheme 1) [26,32,34]. Of interest, compound Cpd-12, bearing an L-thiazolidyl ester side chain, and analogs Cpd-17 to Cpd-20 bearing L-and D-prolyl ester side chains displayed a 10-fold lower MIC against M. tb growth and also improved inhibitory concentrations, i.e., IC50 values of 0.2-0.8 µM toward Cut6, compared with Orlistat (IC50 = 3.8 µM) [26].…”

Section: Mycobacterial Lipolytic Enzyme Inhibitors Are Promising Antituberculous Candidatesmentioning

confidence: 99%

Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery

Cavalier

Spilling

Camoin

et al. 2021

European Journal of Medicinal Chemistry

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Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains the deadliest infectious disease worldwide with 1.5 million deaths in 2018, of which about 15% are attributed to resistant strains. Another significant example is Mycobacterium abscessus (M. abscessus), a nontuberculous mycobacteria (NTM) responsible for cutaneous and pulmonary infections, representing up to 95% of NTM infections in cystic fibrosis (CF) patients. M. abscessus is a new clinically relevant pathogen and is considered one of the most drug-resistant mycobacteria for which standardized chemotherapeutic regimens are still lacking. Together the emergence of M. tb and M. abscessus multi-drug resistant strains with ineffective and expensive therapeutics, have paved the way to the development of new classes of anti-mycobacterial agents offering additional therapeutic options. In this context, specific inhibitors of mycobacterial lipolytic enzymes represent novel and promising antibacterial molecules to address this challenging issue. The results highlighted here include a complete overview of the antibacterial activities, either in broth medium or inside infected macrophages, of two families of promising and potent anti-mycobacterial multi-target agents, i.e. oxadiazolone-core compounds (OX) andCyclophostin & Cyclipostins analogs (CyC) ; the identification and biochemical validation of their effective targets (e.g., the antigen 85 complex and TesA playing key roles in mycolic acid metabolism) together with their respective crystal structures. To our knowledge, these are the first families of compounds able to target and impair replicating as well as intracellular bacteria.We are still impelled in deciphering their mode of action and finding new potential therapeutic targets against mycobacterial-related diseases.

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Section: Mycobacterial Lipolytic Enzyme Inhibitors Are Promising Antituberculous Candidatesmentioning

confidence: 99%

Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery

Cavalier

Spilling

Camoin

et al. 2021

European Journal of Medicinal Chemistry

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“…TLC of total mycolates in the depleted strains compared to induced strains did not show changes when normalized to whole cell lipids (S3A Fig). We then used a newly developed method to examine de novo synthesis of mycolates by mass spectrometry of cells grown in the presence of 13 C acetate [32] (Fig 5B). This assay works on the principle that collision induced dissociation mass spectrometry allows reliable isolation of a precursor molecule in a narrow mass window, which largely removes signals from naturally occurring isotopes, allowing new isotopes from 13 C labeling to be reliably identified.…”

Section: Plos Pathogensmentioning

confidence: 99%

“…tuberculosis wild type and all three depletion mutants were cultured in 7H9+ADN medium to early exponential phase. Bacteria were then harvested according to published methods [32]. Briefly, pellets were washed three times in 10 ml distilled water and then resuspended in 15 ml methanol/chloroform (2:1) for 24 hours for sterilization and lipid extraction.…”

Section: Total Lipid Extraction Cell Wall-bound Mycolic Acids (Ma) Imentioning

confidence: 99%

“…Biological duplicate samples for TLC were harvested at serial time points by resuspending the bacteria into 15 mL 1:2 (V:V) chloroform:methanol to sterilize samples and extract lipids. Total mycolates were isolated by saponification as previously described [32], dried down under nitrogen and analyzed by TLC (Silica Gel 60, Macherey-Nagel) using 3 developments with 90:15 (v/v) hexane: diethyl ether and developed with 8% (v/v) phosphoric acid and 3% (w/v) cupric acetate and charring. S3B) Detection of newly synthesized fatty acids using 13 C labeling of wild type and kinase depletion strains.…”

Section: S2 Fig Viability Over Time Of Wild Type and Kinase Depletiomentioning

confidence: 99%

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Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility

et al. 2020

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The Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB are essential for growth and have been proposed as possible drug targets. We used a titratable conditional depletion system to investigate the functions of these kinases. Depletion of PknA or PknB or both kinases resulted in growth arrest, shortening of cells, and time-dependent loss of acidfast staining with a concomitant decrease in mycolate synthesis and accumulation of trehalose monomycolate. Depletion of PknA and/or PknB resulted in markedly increased susceptibility to β-lactam antibiotics, and to the key tuberculosis drug rifampin. Phosphoproteomic analysis showed extensive changes in protein phosphorylation in response to PknA depletion and comparatively fewer changes with PknB depletion. These results identify candidate substrates of each kinase and suggest specific and coordinate roles for PknA and PknB in regulating multiple essential physiologies. These findings support these kinases as targets for new antituberculosis drugs and provide a valuable resource for targeted investigation of mechanisms by which protein phosphorylation regulates pathways required for growth and virulence in M. tuberculosis.

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“…[49][50] was employed to capture and identify candidate target enzyme(s) impacted by CyC17 and CyC26, the two best hits acting against extracellular M. abscessus.In the first approach, a crude lysate of M. abscessus R was incubated with either a CyC inhibitor (or DMSO as a control) and subjected to a competitive probe labeling/enrichment assay with a Desthiobiotin-FP probe (see Supplementary…”

mentioning

confidence: 99%

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus

et al. 2019

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Twelve new Cyclophostin and Cyclipostins analogs (CyC19-30) were synthesized, thus extending our series to 38 CyCs. Their antibacterial activities were evaluated against four pathogenic mycobacteria (Mycobacterium abscessus, Mycobacterium marinum, Mycobacterium bovis BCG and Mycobacterium tuberculosis) and two Gram negative bacteria. The CyCs displayed very low toxicity towards host cells and were only active against mycobacteria. Importantly, several CyCs were active against extracellular M. abscessus (CyC17/CyC18β/CyC25/CyC26) or intramacrophage residing mycobacteria (CyC7(α,β)/CyC8(α,β)) with minimal inhibitory concentrations (MIC50) values comparable to or better than those of amikacin or imipenem, respectively. An activity-based protein profiling combined with mass spectrometry allowed identification of the potential target enzymes of CyC17/CyC26, mostly being involved in lipid metabolism and/or in cell wall biosynthesis. Overall, these results strengthen the selective activity of the CyCs against mycobacteria, including the most drug-resistant M. abscessus, through the cumulative inhibition of a large number of Ser-and Cysenzymes participating in key physiological processes.

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Ein antibakterielles β‐Lacton bekämpft Mycobacterium tuberculosis durch Infiltration der Mykolsäurebiosynthese

Cited by 5 publications

References 37 publications

Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery

Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery

Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus

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