Inhibition of Pantothenate Synthetase by Analogs of β-Alanine Precursor Ineffective as an Antibacterial Strategy

Liyanage, S. Imindu; Gupta, Mayuri; Wu, Fan; Taylor, Marcy; Carter, Michael D.; Weaver, Donald F.

doi:10.1159/000499899

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…While all organisms synthesize CoA, humans cannot synthesize pantothenate de novo , offering therefore a bacteria-specific target. Such a strategy was previously considered (49,50), but sidelined because antimicrobial susceptibility testing failed to show in vitro growth inhibition of bacteria treated with competitive inhibitors of pantothenate synthetase (51,52). It was suggested that either pantothenate synthetase was not susceptible to inhibition or its inhibition was irrelevant to bacterial survival and growth.…”

Section: Discussionmentioning

confidence: 99%

ThepanC-encoded pantothenate synthetase to tackle carbapenem-resistant OprDPseudomonas aeruginosamutant revealed through Tn-Seq

Van Maele,

Caboche,

Moutel

et al. 2023

Preprint

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For the World Health Organization, carbapenem-resistant Pseudomonas aeruginosa is a critical priority for which new antimicrobial drugs are needed. Consequently, understanding the underlying mechanisms of resistant bacteria infection will enable the identification of new therapeutic targets. Loss of the OprD porin is the main determinant of resistance to the last resort carbapenem antibiotics and has been described to enhance fitness in vivo and virulence. Transposon sequencing is a high-throughput sequencing technique that makes it possible to identify essential genes (EGs) that may turn out to be therapeutic targets. However, such a strategy has not yet been used for OprD-deficient P. aeruginosa. In this study, we identified the EGs specific to PA14 OprD mutant for LB growth and highlighted the panC gene encoding pantothenate synthetase as a promising target. We established a list of 30 EGs of PA14 OprD mutant. Using CRISPRi, we confirmed that silencing panC reduced LB growth, and decreased sigX expression, whose overexpression is associated with membrane fluidity, as well as the expression of genes involved in the fatty acid synthesis (FAS). Taking into account the weakness of PA14 OprD mutant due to an altered membrane consecutive to a decrease in unsaturated FAS in the absence of panC, we showed that silencing panC extended the time of death of human bronchial epithelial cells (16HBE). Overall, our findings highlighted the anti-virulence potential of panC inhibition and shed new light on its inhibition as a target for treating carbapenem-resistant OprD-defective PA lung infections.

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Section: Discussionmentioning

confidence: 99%

ThepanC-encoded pantothenate synthetase to tackle carbapenem-resistant OprDPseudomonas aeruginosamutant revealed through Tn-Seq

Van Maele,

Caboche,

Moutel

et al. 2023

Preprint

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“…While no inhibitors have been reported for MtPPAT using structure-based approaches, inhibitors have been described for EcPPAT, its homologue from E. coli (Zhao et al, 2003;Miller et al, 2010;Moreau et al, 2018;Skepper et al, 2018;Liyanage et al, 2019;Wang et al, 2020). The two homologues share 44% identity and 77% similarity in their amino acid sequences, and both exist as hexamers in their active form (Timofeev et al, 2010).…”

Section: Ppat Inhibitors Developed Through Rational Designmentioning

confidence: 99%

Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents

Butman

Kotze

Dowd

et al. 2020

Front. Cell. Infect. Microbiol.

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Despite decades of dedicated research, there remains a dire need for new drugs against tuberculosis (TB). Current therapies are generations old and problematic. Resistance to these existing therapies results in an ever-increasing burden of patients with disease that is difficult or impossible to treat. Novel chemical entities with new mechanisms of action are therefore earnestly required. The biosynthesis of coenzyme A (CoA) has long been known to be essential in Mycobacterium tuberculosis (Mtb), the causative agent of TB. The pathway has been genetically validated by seminal studies in vitro and in vivo. In Mtb, the CoA biosynthetic pathway is comprised of nine enzymes: four to synthesize pantothenate (Pan) from l-aspartate and α-ketoisovalerate; five to synthesize CoA from Pan and pantetheine (PantSH). This review gathers literature reports on the structure/mechanism, inhibitors, and vulnerability of each enzyme in the CoA pathway. In addition to traditional inhibition of a single enzyme, the CoA pathway offers an antimetabolite strategy as a promising alternative. In this review, we provide our assessment of what appear to be the best targets, and, thus, which CoA pathway enzymes present the best opportunities for antitubercular drug discovery moving forward.

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A Series of 2‐((1‐Phenyl‐1H‐imidazol‐5‐yl)methyl)‐1H‐indoles as Indoleamine 2,3‐Dioxygenase 1 (IDO1) Inhibitors

et al. 2021

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Dedicated to the memory of Prof. Walter A. SzarekIndoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC 50 = 0.16 μM, EC 50 = 0.3 μM). Structuralactivity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.

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Inhibition of Pantothenate Synthetase by Analogs of β-Alanine Precursor Ineffective as an Antibacterial Strategy

Cited by 5 publications

References 20 publications

ThepanC-encoded pantothenate synthetase to tackle carbapenem-resistant OprDPseudomonas aeruginosamutant revealed through Tn-Seq

ThepanC-encoded pantothenate synthetase to tackle carbapenem-resistant OprDPseudomonas aeruginosamutant revealed through Tn-Seq

Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents

A Series of 2‐((1‐Phenyl‐1H‐imidazol‐5‐yl)methyl)‐1H‐indoles as Indoleamine 2,3‐Dioxygenase 1 (IDO1) Inhibitors

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