Authors
Rayan Aboalgasim Makawi Abdalrahman, Katharina Sophie Erlitz, Joana Massa, Christopher-Nils Mais, Gert Bange, Anna Junker, Oliver Koch
Published in
Archiv der Pharmazie. Volume 359. Issue 10.
Abstract
The bacterial stringent response, mediated by the alarmone nucleotides (p)ppGpp, plays a central role in persistence of infections, stress adaptation, and antimicrobial tolerance, making (p)ppGpp synthetases attractive targets for novel antibacterial strategies/therapies. In this study, we report the design, synthesis, and biological evaluation of fragment-linked nucleobase derivatives targeting the RelA/SpoT homolog (RSH) enzymes. Guided by structural insights into adenine and guanine binding within small alarmone synthetase (SAS2/RelP), a series of purine-based compounds was developed to simultaneously occupy conserved nucleotide-binding regions. Initial linker-bridged analogues showed limited activity, primarily due to poor solubility, prompting the introduction of ribose-containing derivatives to improve physicochemical properties. Biochemical evaluation using HPLC-based assays revealed selective inhibition of Staphylococcus aureus SAS1, with the most potent compound displaying micromolar activity (IC50 = 1.8 µM), while little or no inhibition was observed for related SAS enzymes. Structure-activity relationship analysis highlights the importance of linker length and nucleobase positioning for enzyme selectivity. These findings establish fragment-linked nucleobase scaffolds as a promising starting point for the development of inhibitors targeting (p)ppGpp biosynthesis and the bacterial stringent response.
PMID:
42935083
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.
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