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.
Mikkel S. Svenningsen, Alexandra Veress, Alexander Harms, Namiko Mitarai, and Szabolcs Semsey (2019). Birth and Resuscitation of (p)ppGpp Induced Antibiotic Tolerant Persister Cells. Sci Rep 9(1):6056.
Nathalie Q. Balaban, Sophie Helaine, Kim Lewis, Martin Ackermann, Bree Aldridge, Dan I. Andersson, Mark P. Brynildsen, Dirk Bumann, Andrew Camilli, James J. Collins, Christoph Dehio, Sarah Fortune, Jean-Marc Ghigo, Wolf-Dietrich Hardt, Alexander Harms, Matthias Heinemann, Deborah T. Hung, Urs Jenal, Bruce R. Levin, Jan Michiels, Gisela Storz, Man-Wah Tan, Tanel Tenson, Laurence Van Melderen, and Annelies Zinkernagel (2019). Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol [Epub ahead of print].
Alexander Harms and Médéric Diard (2019). Crowd controlled – host quorum sensing drives phage decision. Cell Host Microbe 25(2):179-181.
Gal Horesh, Alexander Harms, Cinzia Fino, Leopold Parts, Kenn Gerdes, Eva Heinz, and Nicholas R. Thomson (2018). SLING: a tool to search for linked genes in bacterial datasets. Nucleic Acids Res 46(21):e128.
Alexander Harms, Ditlev E. Brodersen, Namiko Mitarai, and Kenn Gerdes (2018). Toxins, targets, and triggers: An overview of toxin-antitoxin biology. Mol Cell 70(5):768-784.
Alexander Harms, Cinzia Fino, Michael A. Sørensen, Szabolcs Semsey, and Kenn Gerdes (2017). Prophages and growth dynamics confound experimental results with antibiotic-tolerant persister cells. mBio 8(6). pii: e01964-17.
Alexander Harms, Marius Liesch, Jonas Körner, Maxime Québatte, Philipp Engel, and Christoph Dehio (2017). A bacterial toxin-antitoxin module is the origin of inter-bacterial and inter-kingdom effectors of Bartonella. PLoS Genet 13(10):e1007077.
Maxime Québatte, Matthias Christen, Alexander Harms, Jonas Körner, Beat Christen, and Christoph Dehio (2017). Gene transfer agent promotes evolvability within the fittest subpopulation of a bacterial pathogen. Cell Syst 4(6):611-621.e6
Alexander Harms, Francisca H. Segers, Maxime Quebatte, Claudia Mistl, Pablo Manfredi, Jonas Körner, Bruno B. Chomel, Michael Kosoy, Soichi Maruyama, Philipp Engel, and Christoph Dehio. (2017). Evolutionary dynamics of pathoadaptation revealed by three independent acquisitions of the VirB/D4 type IV secretion system in Bartonella. Genome Biol Evol 9(3):761-776.
Alexander Harms, Etienne Maisonneuve, and Kenn Gerdes (2016). Mechanisms of bacterial persistence during stress and antibiotic exposure. Science 16;354(6318).
Alexander Harms and Kenn Gerdes (2016). Back to the roots: Deep view into the evolutionary history of ADP-Ribosylation opened by the DNA-targeting toxin-antitoxin module DarTG. Mol Cell 64(6):1020-1021.
Frédéric V. Stanger, Alexander Harms, Christoph Dehio, and Tilman Schirmer (2016). Crystal structure of the Escherichia coli Fic toxin-like protein in complex with its cognate antitoxin. PLoS One 11(9):e0163654.
Alexander Harms, Frédéric V. Stanger, and Christoph Dehio (2016). Biological diversity and molecular plasticity of FIC domain proteins. Annu Rev Microbiol 70:341-60.
Frédéric V. Stanger, Björn M. Burmann, Alexander Harms, Hugo Aragão, Adam Mazur, Timothy Sharpe, Christoph Dehio, Sebastian Hiller, and Tilman Schirmer (2016). Intrinsic regulation of FIC-domain AMP-transferases by oligomerization and automodification. Proc Natl Acad Sci U S A 113(5):E529-37.
Alexander Harms, Frédéric V. Stanger, Patrick D. Scheu, Imke G. de Jong, Arnaud Goepfert, Timo Glatter, Kenn Gerdes, Tilman Schirmer, and Christoph Dehio (2015). Adenylylation of gyrase and topo IV by FicT toxins disrupts bacterial DNA topology. Cell Rep 12(9):1497-507.
Kathrin Pieles, Timo Glatter, Alexander Harms, Alexander Schmidt, and Christoph Dehio (2014). An experimental strategy for the identification of AMPylation targets from complex protein samples. Proteomics. 14 (9):1048-52.
Arnaud Goepfert, Alexander Harms, Tilman Schirmer, and Christoph Dehio (2013). Type II toxin-antitoxin loci: The fic family. K. Gerdes (ed.), Prokaryotic Toxin-Antitoxins, Springer Berlin Heidelberg, 2013, 177-187.
Philipp Engel, Arnaud Goepfert, Frédéric V. Stanger, Alexander Harms, Alexander Schmidt, Tilman Schirmer, and Christoph Dehio (2012). Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins. Nature. 482(7383):107-10.
Alexander Harms and Christoph Dehio (2012). Intruders below the radar: molecular pathogenesis of Bartonella spp. Clin Microbiol Rev. 25(1):42-78.