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NTZDpa (non-thiazolidinedione PPARγ partial agonist) derivatives retain antimicrobial activity without improving renal toxicity.

ABSTRACT: nTZDpa kills both growing and persister Staphylococcus aureus. However, due to toxicity liabilities, our lab conducted two structure-activity relationship (SAR) studies focusing on the core scaffold and obtained a new lead compound that was more potent and less hemolytic. Despite these favorable changes, the new lead displayed toxicity to renal cells. In this SAR study, we sought to improve this renal toxicity by derivatization via changes to sp³ character, the acid moiety, and halogenation of the aryl rings. Presented herein are our efforts that produced potent compounds albeit with no improvement to renal cell toxicity.

SUBMITTER: Dekarske MM

PROVIDER: S-EPMC9019844 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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nTZDpa (non-thiazolidinedione PPARγ partial agonist) derivatives retain antimicrobial activity without improving renal toxicity.

Dekarske Madeline M MM Felix Lewis Oscar LO Ortiz Carlos Monteagudo CM Csatary Erika E EE Mylonakis Elefterios E Wuest William M WM

Bioorganic & medicinal chemistry letters 20220314

nTZDpa kills both growing and persister Staphylococcus aureus. However, due to toxicity liabilities, our lab conducted two structure-activity relationship (SAR) studies focusing on the core scaffold and obtained a new lead compound that was more potent and less hemolytic. Despite these favorable changes, the new lead displayed toxicity to renal cells. In this SAR study, we sought to improve this renal toxicity by derivatization via changes to sp<sup>3</sup> character, the acid moiety, and haloge ...[more]

PMID: 35301137

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Project description:Peroxisome proliferator activated receptor gamma (PPARγ) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARγ protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARγ full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARγ agonist with insulin-sensitizing and a weak pro-adipocytic activity. TEL decreased S273pPPARγ and did not affect S112pPPARγ levels in a model of marrow MSC differentiation, U-33/γ2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARγ. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced "browning" of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARγ acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARγ agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARγ fat "browning" activity and a lack of anti-osteoblastic activity.

Dataset Information

NTZDpa (non-thiazolidinedione PPARγ partial agonist) derivatives retain antimicrobial activity without improving renal toxicity.

Publications

nTZDpa (non-thiazolidinedione PPARγ partial agonist) derivatives retain antimicrobial activity without improving renal toxicity.

Similar Datasets

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