AbstractPantothenamides are potent growth inhibitors of the malaria parasite Plasmodium falciparum. Their clinical use is, however, hindered due to the ubiquitous presence of pantetheinases in human serum, which rapidly degrade pantothenamides into pantothenate and the corresponding amine. We previously reported that replacement of the labile amide bond with a triazole ring not only imparts stability toward pantetheinases, but also improves activity against P. falciparum. A small library of new triazole derivatives was synthesized, and their use in establishing structure–activity relationships relevant to antiplasmodial activity of this family of compounds is discussed herein. Overall it was observed that 1,4‐substitution on the triazole ring and use of an unbranched, one‐carbon linker between the pantoyl group and the triazole are optimal for inhibition of intraerythrocytic P. falciparum growth. Our results imply that the triazole ring may mimic the amide bond with an orientation different from what was previously suggested for this amide bioisostere.

2018-05-11·ACS Infectious Diseases2区 · 医学

Developing Pantetheinase-Resistant Pantothenamide Antibacterials: Structural Modification Impacts on PanK Interaction and Mode of Action

2区 · 医学

Article

作者: Strauss, Erick ; van Otterlo, Willem A. L. ; Barnard, Leanne ; Mostert, Konrad J.

Pantothenamides (PanAms) are analogues of pantothenate, the biosynthetic precursor of coenzyme A (CoA), and show potent antimicrobial activity against several bacteria and the malaria parasite in vitro. However, pantetheinase enzymes that normally degrade pantetheine in human serum also act on the PanAms, thereby reducing their potency. In this study, we designed analogues of the known antibacterial PanAm N-heptylpantothenamide (N7-Pan) to be resistant to pantetheinase by using three complementary structural modification strategies. We show that, while two of these are effective in imparting resistance, the introduced modifications have an impact on the analogues' interaction with pantothenate kinase (PanK, the first CoA biosynthetic enzyme), which acts as a metabolic activator and/or target of the PanAms. This, in turn, directly affects their mode of action. Importantly, we discover that the phosphorylated version of N7-Pan shows pantetheinase resistance and antistaphylococcal activity, providing a lead for future studies in the ongoing search of PanAm analogues that show in vivo efficacy.

2016-09-09·ACS Infectious Diseases2区 · 医学

Discovery of Potent Pantothenamide Inhibitors of Staphylococcus aureus Pantothenate Kinase through a Minimal SAR Study: Inhibition Is Due to Trapping of the Product

2区 · 医学

Article

作者: Hughes, Scott J. ; Mottaghi, Katayoun ; Antoshchenko, Tetyana ; Barnard, Leanne ; Tempel, Wolfram ; Smil, David ; Park, Hee-Won ; Hong, Bum Soo ; Strauss, Erick ; Vedadi, Masoud ; Allali-Hassani, Abdellah

The potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) has been shown to at least partially be due to the inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanK_II), the first enzyme of coenzyme A biosynthesis. This mechanism of action follows from SaPanK_II having a binding mode for PanAms that is distinct from those of other PanKs. To dissect the molecular interactions responsible for PanAm inhibitory activity, we conducted a mini SAR study in tandem with the cocrystallization of SaPanK_II with two classic PanAms (N5-Pan and N7-Pan), culminating in the synthesis and characterization of two new PanAms, N-Pip-PanAm and MeO-N5-PanAm. The cocrystal structures showed that all of the PanAms are phosphorylated by SaPanK_II but remain bound at the active site; this occurs primarily through interactions with Tyr240' and Thr172'. Kinetic analysis showed a strong correlation between k_cat (slow PanAm turnover) and IC₅₀ (inhibition of pantothenate phosphorylation) values, suggesting that SaPanK_II inhibition occurs via a delay in product release. In-depth analysis of the PanAm-bound structures showed that the capacity for accepting a hydrogen bond from the amide of Thr172' was a stronger determinant for PanAm potency than the capacity to π-stack with Tyr240'. The two new PanAms, N-Pip-PanAm and MeO-N5-PanAm, effectively combine both hydrogen bonding and hydrophobic interactions, resulting in the most potent SaPanK_II inhibition described to date. Taken together, our results are consistent with an inhibition mechanism wherein PanAms act as SaPanK_II substrates that remain bound upon phosphorylation. The phospho-PanAm-SaPanK_II interactions described herein may help future antistaphylococcal drug development.

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