Deep phosphoproteomics of Klebsiella pneumoniae reveals HipA-mediated tolerance to ciprofloxacin

Payal Nashier, Isabell Samp, Marvin Adler, Fiona Ebner, Lisa Thai Lê, Marc Göppel, Carsten Jers, Ivan Mijakovic, Sandra Schwarz, Boris Macek

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Abstract

Klebsiella pneumoniae belongs to the group of bacterial pathogens causing the majority of antibiotic-resistant nosocomial infections worldwide; however, the molecular mechanisms underlying post-translational regulation of its physiology are poorly understood. Here we perform a comprehensive analysis of Klebsiella phosphoproteome, focusing on HipA, a Ser/ Thr kinase involved in antibiotic tolerance in Escherichia coli. We show that overproduced K. pneumoniae HipA (HipAkp) is toxic to both E. coli and K. pneumoniae and its toxicity can be rescued by overproduction of the antitoxin HipBkp. Importantly, HipAkp overproduction leads to increased tolerance against ciprofloxacin, a commonly used antibiotic in the treatment of K. pneumoniae infections. Proteome and phosphoproteome analyses in the absence and presence of ciprofloxacin confirm that HipAkp has Ser/Thr kinase activity, autophosphorylates at S150, and shares multiple substrates with HipAec, thereby providing a valuable resource to clarify the molecular basis of tolerance and the role of Ser/Thr phosphorylation in this human pathogen.
Original languageEnglish
JournalPLOS Pathogens
Volume20
Issue number12
Pages (from-to)e1012759
ISSN1553-7366
DOIs
Publication statusPublished - 2024

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