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When a phage structural protein does more than build the virus
Bacteria use the stringent response, a global stress-response pathway controlled by the alarmone nucleotides ppGpp and pppGpp, to slow growth and resist diverse stresses. We found that this pathway can also restrict bacteriophage infection. In response, phages have evolved a surprising counter-strategy: their portal proteins, best known as structural components that help package DNA into viral particles, can directly target the bacterial RelA/SpoT enzymes that produce alarmones. By inhibiting stringent-response signaling, these phage proteins accelerate infection and help overcome a host physiological barrier. This work reveals an unexpected non-structural function of phage portal proteins and shows how phages can actively reshape bacterial stress physiology during infection.
Phage Therapy via Receptor-Constrained Evolutionary Traps
In this work, we propose that phage therapy should not only be viewed as a way to kill bacterial pathogens directly, but also as a strategy to shape bacterial evolution. Many phages recognize specific receptors on the bacterial surface. When these receptors are functionally important for virulence, antibiotic resistance, immune evasion, or fitness, bacterial escape from phage attack may come at a cost.
This leads to the concept of receptor-constrained evolutionary traps: by selecting phages that target key bacterial receptors, therapy may force pathogens into evolutionary routes that make them less harmful or more vulnerable to antibiotics, host immunity, or other treatments.
We hope this framework will help support more rational, evolution-informed design of phage therapy strategies against antimicrobial-resistant infections.
Novel binding proteins of Cyclic AMP coordinate growth and competence of Haemophilus influenzae
JBC 2023
Haemophilus influenzae can acquire antibiotic resistance through natural competence, a process that enables bacteria to take up and integrate external DNA. We show that cyclic AMP promotes competence by inhibiting periplasmic phosphatases, thereby limiting the use of external nucleotides and NAD. This mechanism links nutrient depletion and growth arrest to DNA uptake. Similar regulation may occur in related bacteria, including Vibrio cholerae.
ppGpp stimulates PpnN to balance competitive growth and persistence
During stringent response, ppGpp feedback inhibits numerous enzymes involved in the purine nucleotide biosynthesis, including both the de novo and salvage pathways. Recently, we surprisingly found a nucleosidase PpnN, cleaving NMP to nucleobases, as a target protein of ppGpp. By integrative use of biochemistry, crystallography, metabolomics and physiology, we discovered that ppGpp allosterically stimulate the catalytic activity of PpnN, which regulates E. coli in achieving balanced adaptation to constantly changing environments with fluctuating levels of nutrient and stress. Such a mechanism is highly conserved in Proteobacteria including many important pathogens.
Novel ppGpp target proteins
mBio 2018
The universal stringent alarmone ppGpp plays pivotal roles in bacterial tolerance to stresses including antibiotic insults. However, mechanistic understandings of ppGpp functions have been hampered by the incomplete knowledge of its target proteins. Using a systems biology tool called DRaCALA, we recently identified many novel ppGpp binding proteins in E. coli, a milestone since the first discovery of ppGpp over 50 years ago. Current work focuses on in depth understanding of ppGpp and its target proteins in bacterial stress response and persistence.
List of Publications
Kristina Kronborg#, Luokai Wang#, Muriel Leandra Schicketanz, Kenn Gerdes, Yong E. Zhang*. Phage portal proteins counteract stringent-response-mediated restriction. Nature Communications (article in press) 2026 https://www.nature.com/articles/s41467-026-75532-5#author-information
Yong E. Zhang*, Youming Zhang. Phage Therapy via Receptor-Constrained Evolutionary Traps. Trends in Microbiology, 04 Jun 2026 (published online). DOI: 10.1016/j.tim.2026.05.011
René L. Bærentsen#, Kristina Kronborg#, Ditlev E Brodersen, Yong E. Zhang*. Catalytic Mechanism and Differential Alarmone Regulation of a Conserved Stringent Nucleosidase 2025-04-14. Structure 34, 198-209 e194 (2026). https://doi.org/10.1016/j.str.2025.10.012
Yong E. Zhang. Protein Kinases in Mediating Phage-Bacteria Interactions. Kinases Phosphatases 2025, 3(3),14. https://doi.org/10.3390/kinasesphosphatases3030014
Muriel Leandra Schicketanz, Magdalena Petrova, Dominik Rejman, Margherita Sosio, Stefano Donadio, Yong E. Zhang*. Direct detection of stringent alarmones (pp)pGpp using malachite green. 2024 Microbial Cell 11: 312-320. doi: 10.15698/mic2024.08.834
Kristina Kronborg, Yong E. Zhang*. Unresolved mystery of cyclic nucleotide second messengers, periplasmic acid phosphatases and bacterial natural competence. 2024 Microbial Cell 11: 235-241. doi: 10.15698/mic2024.07.828
Kristina Kronborg, Yong E. Zhang*. Substrate promiscuity of the Escherichia coli xanthine oxidase. Dec 2023. bioRxiv doi: https://doi.org/10.1101/2023.12.06.570370
Kristina Kronborg, Yong E. Zhang*. Cyclic AMP competitively inhibits periplasmic phosphotases to coordinate nutritional growth and competence of Haemophilus influenzae. J Bio Chem. 2023 Oct 26. DOI: 10.1016/j.jbc.2023.105404
(Editors’ Pick)Paulina Katarzyna Grucela, Yong E. Zhang*. Basal level of ppGpp coordinates Escherichia coli cell heterogeneity and ampicillin resistance and persistence. Microbial Cell. 2023 Oct 25; 10(11): 248-260. doi: 10.15698/mic2023.11.808.
Paulina Katarzyna Grucela, Tobias Fuhrer, Uwe Sauer, Yanjie Chao* and Yong E. Zhang*. Ribose 5-phosphate: the key metabolite bridging the metabolisms of nucleotides and amino acids during stringent response in Escherichia coli? Microbial Cell. 2023 Jun 1;10(7):141-144. doi: 10.15698/mic2023.07.799. eCollection 2023 Jul 3.
Kristina Kronborg, Yong E. Zhang*. Cyclic AMP competitively inhibits three periplasmic acid phosphotases to regulate cell growth and competence of Haemophilus influenzae. 24 Aug 2022 bioRxiv, doi: https://doi.org/10.1101/2022.08.24.505078
Ziwei Liang, Morten Rybtke, Kasper Nørskov Kragh, Owen Johnson, Muriel Schicketanz, Yong E. Zhang, Jens Bo Andersen, Tim Tolker-Nielsen. Transcription of the alginate operon in Pseudomonas aeruginosa is regulated by c-di-GMP. 2022 Microbial Spec (DOI: https://doi.org/10.1128/spectrum.00675-22)
Francesco Bisiak, Adriana Chrenková, Sheng-Da Zhang, Jannik N. Pedersen, Daniel E. Otzen, Yong E. Zhang, Ditlev E. Brodersen*. Structural variations between small alarmone hydrolase dimers support different modes of regulation of the stringent response. J Bio Chem. 2022 DOI:https://doi.org/10.1016/j.jbc.2022.102142
Muriel L. Schicketanz, Paulina Długosz, Yong E. Zhang*. Identifying the Binding Proteins of Small Ligands with the Differential Radial Capillary Action of Ligand Assay (DRaCALA). JoVE. 2021 Mar 19;(169). doi: 10.3791/62331.
N. Y Elizabeth Chau, Deyanira Pérez-Morales, Wael Elhenawy, Víctor H. Bustamante, Yong E. Zhang, Brian K. Coombes* (p)ppGpp-dependent regulation of the nucleotide hydrolase PpnN confers complement resistance in Salmonella enterica serovar Typhimurium. Infection & Immunity. 2021 Jan 19;89(2):e00639-20. doi: 10.1128/IAI.00639-20.
René L Bærentsen, Ditlev E. Brodersen and Yong E. Zhang*. Evolution of the bacterial nucleosidase PpnN and its relation to the stringent response. Microbial Cell. 2019. 6(9), 450-453. (invited microreview)
Zhang E. Yong#*, Bærentsen L Rene#, Tobias Fuhrer, Uwe Sauer, Kenn Gerdes, Brodersen E. Ditlev*. (p)ppGpp regulates a bacterial nucleosidase by an allosteric two-domain switch. Molecular Cell (2019). 74(6):1239-1249.e4 (*co-corresponding author; # equal contribution))
Mathilde Guzzo, SeánM. Murray, Eugénie Martineau, Sébastien Lhospice, Grégory Baronian, Laetitia My, Yong Zhang, Leon Espinosa, Renaud Vincentelli, Benjamin P. Bratton, Joshua W. Shaevitz, Virginie Molle, Martin Howard, Tâm Mignot. A gated relaxation oscillator mediated by FrzX controls morphogenetic movements in Myxococcus xanthus. Nature Microbiology. 2018 Aug;3(8):948-959.
Yong Zhang*, Eva Zborníková, Dominik Rejman and Kenn Gerdes*. Novel (p)ppGpp binding and metabolizing proteins of Escherichia coli. 2018. mBio 9:e02188-17. (*co-corresponding author)
Yong Zhang, Rym Agrebi, Lauren E Bellows, Jean-François Collet, Volkhard Kaever, Angelika Gründling*. Evolutionary Adaptation of the Essential tRNA Methyltransferase TrmD to the Signaling Molecule 3′, 5′-cAMP in Bacteria. J Bio Chem. 2017 Jan 6;292(1):313-327.
Joana A. Moscoso, Hannal Schramke, Yong Zhang, Amina Dehbi, Kirsten Jung and Angelika Gründling*. Binding of Cyclic Di-AMP to the Staphylococcus aureus Sensor Kinase KdpD Occurs via the Universal Stress Protein Domain and Downregulates the Expression of the Kdp Potassium Transporter. Journal of Bacteriology. 2015 Jul 20;198(1):98-110.
Ivan Campeotto#, Yong Zhang#, Miroslav G. Mladenov, Paul S. Freemont* and Angelika Gründling*. Complex Structure and Biochemical Characterization of the Staphylococcus aureus Cyclic Diadenylate Monophosphate (c-di-AMP)-binding Protein PstA, the Founding Member of a New Signal Transduction Protein Family. J Bio Chem. 2015 Jan 30; 290(5): 2888–2901. (# equal contribution)
Yong Zhang, Mathilde Guzzo, Adrien Ducret, Yue-Zhong Li, Tâm Mignot*. A dynamic response regulator protein modulates G protein-dependent polarity in the bacterium Myxococcus xanthus. PLoS Genetics. 2012 August; 8(8): e1002872.
Yong Zhang, Adrien Ducret, Joshua Shaevitz and Tâm Mignot*. From individual cell motility to collective behaviors: insights from a prokaryote, Myxococcus xanthus. FEMS Microbiology Review. 2012 Jan;36(1):149-64.
Yong Zhang, Michel Franco, Adrien Ducret and Tâm Mignot*. A bacterial Ras-like small GTP-binding protein and its cognate GAP establish a dynamic spatial polarity axis to control directed motility. PLoS Biology. 2010 Jul 20; 8(7): e1000430. Highlighted at PLoS Biology with a synopsis.
Hong-Wei Pan, Hong Liu, Ting Liu, Cheng-Yun Li, Zhi-Feng Li, Ke Cai, Cui-Ying Zhang, Yong Zhang, Wei Hu, Zhi-Hong Wu, Yue-hong Li*. Seawater-regulated genes for two- component systems and outer membrane proteins in Myxococcus. Journal of Bacteriology. 2009. 191(7):2102-11
Cui-ying Zhang, Ke Cai, Hong Liu, Yong Zhang, Hong-wei Pan, Bing Wang, Zhi-Hong Wu, Wei Hu, and Yue-zhong Li*. New Locus Important for Myxococcus Social Motility and Development. Journal of Bacteriology. 2007. 189(21): 7937-41.
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