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Defeating antibiotic tolerant pathogens with bacteriophages

Our research aims at learning from bacteriophages how to fight bacterial infections when antibiotics are ineffective.

Viruses infecting bacteria, so-called bacteriophages, are the most abundant and diverse biological entities on earth. They have continuously evolved to be the deadliest predators of bacteria for hundreds of millions of years. Consequently, the therapeutic potential of bacteriophages is increasingly recognized as a powerful alternative to conventional antibiotics.

Chronic infections are highly resilient to antibiotic treatment
Bacteriophages have moved into the spotlight as allies in the fight against antibiotic resistance. However, the treatment of chronic infections often fails not because the bacteria are resistant but rather because they are in a highly drug-tolerant, slow-growing “dormant” state. Our research studies new ways of clearing both antibiotic-resistant and antibiotic-tolerant infections with the help of bacteriophages.

Where antibiotics fail, bacteriophages succeed
Starting from environmental samples, we isolate and characterize bacteriophages with the ability to overpower and kill highly drug-tolerant or -resistant, dormant pathogens. A wide range of techniques is used study the infection of these cells with bacteriophages from a molecular, cellular, and evolutionary viewpoint. Our aim is to understand the long-evolved strategies of bacteriophages to overcome or bypass the obstacles inherent to a dormant bacterial physiology.

Bacteriophages inspire novel strategies for treating chronic infections
We anticipate that unraveling these bacteriophage strategies will highlight previously overlooked Achilles’ heels of antibiotic-resistant and -tolerant bacteria that could guide the development of new therapeutics for chronic infections.

Team

PhD Students

Master Students

Publications

2020

Horesh, Gal; Fino, Cinzia; Harms, Alexander; Dorman, Matthew J.; Parts, Leopold; Gerdes, Kenn; Heinz, Eva; Thomson, Nicholas R. (2020). Type II and type IV toxin-antitoxin systems show different evolutionary patterns in the global Klebsiella pneumoniae population. Nucleic Acids Research, 48 (8), 4357-4370.

Sorg, Isabel; Schmutz, Christoph; Lu, Yun-Yueh; Fromm, Katja; Siewert, Lena K.; Bögli, Alexandra; Strack, Kathrin; Harms, Alexander; Dehio, Christoph (2020). A Bartonella effector acts as signaling hub for intrinsic STAT3 activation to trigger anti-inflammatory responses. Cell host & microbe, 27 (3), 476-485.

2019

Balaban, N. Q.; Helaine, S.; Lewis, K.; Ackermann, M.; Aldridge, B.; Andersson, D. I.; Brynildsen, M. P.; Bumann, D.; Camilli, A.; Collins, J. J.; Dehio, C.; Fortune, S.; Ghigo, J. M.; Hardt, W. D.; Harms, A.; Heinemann, M.; Hung, D. T.; Jenal, U.; Levin, B. R.; Michiels, J.; Storz, G.; Tan, M. W.; Tenson, T.; Van Melderen, L.; Zinkernagel, A. (2019). Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol, 17 (7), 441-448.

Svenningsen, M. S.; Veress, A.; Harms, A.; Mitarai, N.; Semsey, S. (2019). Birth and Resuscitation of (p)ppGpp Induced Antibiotic Tolerant Persister Cells. Sci Rep, 9 (1), 6056.

Harms, A.; Diard, M. (2019). Crowd Controlled-Host Quorum Sensing Drives Phage Decision. Cell Host Microbe, 25 (2), 179-181.

Harms, Alexander: The Biology of Persister Cells in Escherichia coli, in: Lewis, Kim(Ed.). (2019). Persister Cells and Infectious Disease, Cham: Springer Nature, 39-57.

2018

Horesh, G.; Harms, A.; Fino, C.; Parts, L.; Gerdes, K.; Heinz, E.; Thomson, N. R. (2018). SLING: a tool to search for linked genes in bacterial datasets. Nucleic Acids Res, 46 (21), e128.

Harms, A.; Brodersen, D. E.; Mitarai, N.; Gerdes, K. (2018). Toxins, Targets, and Triggers: An Overview of Toxin-Antitoxin Biology. Molecular cell, 70 (5), 768-784.

2017

Harms, Alexander; Fino, Cinzia; Sørensen, Michael A.; Semsey, Szabolcs; Gerdes, Kenn (2017). Prophages and Growth Dynamics Confound Experimental Results with Antibiotic-Tolerant Persister Cells. MBio, 8 (6), ii:e01964-17.

Harms, Alexander; Liesch, Marius; Körner, Jonas; Québatte, Maxime; Engel, Philipp; Dehio, Christoph (2017). A bacterial toxin-antitoxin module is the origin of inter-bacterial and inter-kingdom effectors of Bartonella. PLoS Genetics, 13 (10), e1007077.

Québatte, Maxime; Christen, Matthias; Harms, Alexander; Körner, Jonas; Christen, Beat; Dehio, Christoph (2017). Gene Transfer Agent Promotes Evolvability within the Fittest Subpopulation of a Bacterial Pathogen. Cell Systems, 4 (6), 611-621.e6.

Harms, Alexander; Segers, Francisca H. I. D.; Quebatte, Maxime; Mistl, Claudia; Manfredi, Pablo; Körner, Jonas; Chomel, Bruno B.; Kosoy, Michael; Maruyama, Soichi; Engel, Philipp; Dehio, Christoph (2017). Evolutionary Dynamics of Pathoadaptation Revealed by Three Independent Acquisitions of the VirB/D4 Type IV Secretion System in Bartonella. Genome biology and evolution, 9 (3), 761-776.

2016

Harms, A.; Maisonneuve, E.; Gerdes, K. (2016). Mechanisms of bacterial persistence during stress and antibiotic exposure. Science, 354 (6318), ii:aaf4268.

Harms, A.; Gerdes, K. (2016). Back to the Roots: Deep View into the Evolutionary History of ADP-Ribosylation Opened by the DNA-Targeting Toxin-Antitoxin Module DarTG. Molecular cell, 64 (6), 1020-1021.

Stanger, F. V.; Harms, A.; Dehio, C.; Schirmer, T. (2016). Crystal Structure of the; Escherichia coli; Fic Toxin-Like Protein in Complex with Its Cognate Antitoxin. PLoS One, 11 (9), e0163654.

Stanger, Frédéric V.; Burmann, Björn M.; Harms, Alexander; Aragão, Hugo; Mazur, Adam; Sharpe, Timothy; Dehio, Christoph; Hiller, Sebastian; Schirmer, Tilman (2016). Intrinsic regulation of FIC-domain AMP-transferases by oligomerization and automodification. Proceedings of the National Academy of Sciences of the United States of America, 113 (5), E529-37.

Swiss Institute of Bioinformatics Members, SIB (2016). The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases. Nucleic acids research, 44 (D1), D27-D37.

Harms, Alexander; Stanger, Frédéric Valentin; Dehio, Christoph (2016). Biological Diversity and Molecular Plasticity of FIC Domain Proteins. Annual Reviews of Microbiology, 70, 341-60.

2015

Harms, Alexander; Stanger, Frédéric Valentin; Scheu, Patrick Daniel; de Jong, Imke Greet; Goepfert, Arnaud; Glatter, Timo; Gerdes, Kenn; Schirmer, Tilman; Dehio, Christoph (2015). Adenylylation of Gyrase and Topo IV by FicT Toxins Disrupts Bacterial DNA Topology. Cell Reports, 12 (9), 1497-507.

2014

Pieles, K.; Glatter, T.; Harms, A.; Schmidt, A.; Dehio, C. (2014). An experimental strategy for the identification of AMPylation targets from complex protein samples. Proteomics, 14 (9), 1048-52.

2013

Goepfert, Arnaud; Harms, Alexander; Schirmer, Tilman; Dehio, Christoph: Type II Toxin-Antitoxin Loci: The fic Family, in: Gerdes, Kenn(Ed.). (2013). Prokaryotic Toxin-Antitoxins, Heidelberg: Springer Verlag, 177-187.

2012

Harms, A.; Dehio, C. (2012). Intruders below the radar: molecular pathogenesis of; Bartonella; spp. Clinical microbiology reviews, 25 (1), 42-78.

Engel, P.; Goepfert, A.; Stanger, F. V.; Harms, A.; Schmidt, A.; Schirmer, T.; Dehio, C. (2012). Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins. Nature, 482 (7383), 107-10.


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