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

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 P...

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Bibliographic Details
Published in:ACS infectious diseases 2018-05, Vol.4 (5), p.736-743
Main Authors: Barnard, Leanne, Mostert, Konrad J, van Otterlo, Willem A. L, Strauss, Erick
Format: Article
Language:English
Subjects:
Amidohydrolases - chemistry
Amidohydrolases - metabolism
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Drug Discovery
Drug Resistance, Bacterial
Enzyme Activation
Humans
Kinetics
Molecular Structure
Pantothenic Acid - analogs & derivatives
Pantothenic Acid - chemistry
Pantothenic Acid - pharmacology
Structure-Activity Relationship
Substrate Specificity
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Summary: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.
ISSN:2373-8227
2373-8227
DOI:10.1021/acsinfecdis.7b00240