.png)
The effect of negative hysteresis – the sensitisation of bacterial cells through a pre-treatment that enhances the effect of a second antibiotic – in principle makes it possible to achieve a significantly improved response even against critical pathogens such as P. aeruginosa.
Photo Credit: © Christian Urban, Kiel University
Scientific Frontline: Extended "At a Glance" Summary: Negative Hysteresis in Antibiotic Sensitization
The Core Concept: Negative hysteresis is an evolution-informed treatment strategy where an initial exposure to one antibiotic predictably induces a temporary cellular vulnerability in a bacterial pathogen to a second, different antibiotic. In the pathogen Pseudomonas aeruginosa, pretreatment with a β-lactam robustly sensitizes the bacteria to a subsequent aminoglycoside attack.
Key Distinction/Mechanism: Unlike traditional combination therapies or chance collateral sensitivity, negative hysteresis actively induces a compromised cellular state. The initial β-lactam triggers the Cpx envelope stress response system, which damages the bacterial cell membrane and forces an elevated cellular uptake of the incoming aminoglycoside, effectively overriding existing resistance mechanisms.
Major Frameworks/Components:
- Sequential Therapy: Administering specific drugs in a staggered, time-controlled timeline to manipulate bacterial adaptation and vulnerability.
- The Cpx Envelope Stress Response: A critical sensory and regulatory system in bacteria that manages membrane stress and inadvertently regulates the lethal uptake of subsequent antibiotics.
- Evolutionary Therapeutics: Utilizing the principles of evolutionary biology to predict, direct, and constrain a pathogen's ability to mutate and survive.
- Genomic Diversity Targeting: Ensuring the sensitization strategy is robust enough to succeed universally across various genetically distinct and highly resistant strains of a single pathogen.
Branch of Science: Microbiology, Evolutionary Biology, Pharmacology.
Future Application: This approach provides a blueprint for designing highly optimized, time-staggered antibiotic regimens capable of eradicating multi-drug resistant strains and polymicrobial infections in high-risk clinical environments.
Why It Matters: With antimicrobial resistance (AMR) escalating into a global health crisis, discovering robust, universally inducible vulnerabilities in dangerous opportunistic pathogens like Pseudomonas aeruginosa provides physicians with a critical new methodology to clear severe infections and prevent superbug evolution.
.png) |
| Dr Florian Buchholz (back), Dr Surajit Pal and the other co-authors were able to demonstrate that administering a beta-lactam antibiotic first triggers a physiological change in P. aeruginosa, which increases the permeability of the cell walls, allowing a second antibiotic to penetrate and thus making it easier to combat the pathogen. Photo Credit: © Christian Urban, Kiel University |
In a recent study, a research team from Kiel University demonstrated the specific cellular mechanisms that lead to the targeted weakening of bacterial pathogens, thereby increasing the effectiveness of antibiotic treatment.
Antibiotic-resistant pathogens pose one of the greatest threats to public health today. Due to the misuse and overuse of antibacterial agents in recent decades, numerous pathogens have become resistant to antibiotics, including many last-resort antibiotics used to treat particularly severe cases. The cause of this global health crisis lies in the drastically rising rates of antimicrobial resistance (AMR) in bacterial pathogens—put simply, more and more bacteria are becoming resistant to treatment, while the range of reliably effective antibiotics continues to shrink. In the near future, therefore, we face the threat of a post-antibiotic era in which even supposedly harmless infections may no longer be treatable. Experts estimate that by the middle of the century, there could be around 50 million AMR-related deaths worldwide each year.
Health organizations and researchers are therefore working on various strategies to tackle the increasingly serious AMR crisis, including optimizing the use of existing antibiotics and developing new drugs. At Kiel University, scientists are investigating the fundamental mechanisms of resistance evolution—that is, the genetic and nongenetic adaptations of a pathogen to drug exposure. Their aim is to combine existing antibiotics effectively, preserve their efficacy, and inhibit the evolution of resistance.
In a recent study, researchers led by Professor Hinrich Schulenburg from the Evolutionary Ecology and Genetics group at Kiel University used the human pathogen Pseudomonas aeruginosa as a model to investigate how harmful bacteria can be weakened by first administering one antibiotic, thereby significantly enhancing the effectiveness of a second antibiotic. They demonstrated that pretreatment with a beta-lactam antibiotic makes the bacterial cells particularly sensitive to a subsequently administered aminoglycoside antibiotic. This effect, termed negative hysteresis, is based on the induction of so-called membrane stress in the bacterial cell wall, which, through the improved penetration of the second drug, not only ensures the reliable killing of the bacteria but also inhibits their adaptation to the treatment, and thus the evolution of resistance. The Kiel researchers recently published their new findings, in collaboration with international colleagues, in the journal Nature Communications.
.png)
Prof. Hinrich Schulenburg’s research group at Kiel University is investigating the mechanisms of resistance evolution in bacterial pathogens in order to combine existing antibiotics effectively, preserve their efficacy and inhibit the development of resistance for future therapeutic applications.
Photo Credit: © Christian Urban, Kiel University
Pseudomonas Infections Are Becoming Increasingly Problematic
The Gram-negative bacterium P. aeruginosa is an opportunistic pathogen in humans. It causes acute and chronic infections, particularly in hospitalized and immunocompromised patients, often in cases of cystic fibrosis or chronic obstructive pulmonary disease. A particular problem is, on the one hand, the bacterium’s widespread resistance to many antibiotics and, on the other, its ability to adapt rapidly to treatment with newly administered drugs. As a result, an increasing number of P. aeruginosa strains are classified as multidrug-resistant bacteria that have become insensitive to three or more different antibiotics. “The World Health Organization (WHO) therefore classifies P. aeruginosa as a high-priority pathogen for which new treatment options are urgently needed. In our research group, we have been working for years on the mechanisms of resistance evolution in this particular pathogen and wish to further investigate potential treatment approaches based in particular on the principle of negative hysteresis,” says Dr. Florian Buchholz, first author of the study and a member of Schulenburg’s research group.
Treatment Approaches Based on Negative Hysteresis Show Great Potential
Buchholz and colleagues carried out their research as part of the DFG-funded Research Training Group (RTG) TransEvo at Kiel University and have now demonstrated that an initially administered beta-lactam antibiotic triggers a physiological change in the bacteria, causing the cell walls to become more permeable to the second antibiotic. Until now, it was unclear exactly how this nongenetic change is mediated and how reliably it can be triggered in different strains of the bacterium. “Our investigations showed that negative hysteresis represents a general weak spot of P. aeruginosa, which can be triggered even by low doses of the sensitizing antibiotic. This causes damage to the cell envelope, thereby enhancing the effect of the second active substance,” explains Dr. Roderich Roemhild, shared senior author of the study and a former member of the Schulenburg group, now based at the ISTA in Austria. Furthermore, the experiments also demonstrated a particular robustness of the phenomenon across the entire diversity of P. aeruginosa; the effect was therefore present regardless of the genetic differences between the bacterial strains.
Evolutionary Research in Kiel Opens Up New Prospects for Antibiotic Therapy
The new findings from researchers in Schulenburg’s group thus confirm the potential of negative hysteresis: in principle, a significantly improved response against even critical bacterial pathogens can be achieved through the appropriate sequential administration of certain classes of antibiotics. “Overall, we were able to demonstrate that the ‘right’ sequence of drugs promotes the killing of pathogens, limits their ability to adapt, and thereby reduces the evolution of resistance in P. aeruginosa,” summarizes Schulenburg, spokesperson for the Kiel Evolution Center (KEC) as part of Kiel University’s Kiel Life Science (KLS) priority research area. With these and other research findings, the scientists aim to lay the groundwork for developing new strategies based on evolutionary concepts for the sustainable treatment of bacterial infections and the prevention of resistance.
To this end, they can draw on a broad interdisciplinary network in translational evolutionary research under the umbrella of the KEC in the Kiel region. For example, thanks to close cooperation with the Max Planck Institute for Evolutionary Biology in Plön, the recently established Leibniz ScienceCampus “AMR-PLAS” for antibiotic resistance research, and the RTG TransEvo, a nationally unique evolutionary biology hotspot has emerged here. “Through exchanges with these partner institutions, a particularly dynamic scientific environment has developed in recent years, providing important impetus for our ongoing research into resistance evolution. The present study is an example of a particularly fruitful collaboration with international and local colleagues from Klosterneuburg in Austria, Uppsala in Sweden, as well as Lübeck, Großhansdorf, Borstel, Hamburg, and, of course, Kiel, all of whom contributed to the research. Building on these networks, we hope to be able to provide fundamental building blocks for tackling the global antimicrobial resistance crisis in the coming years,” says Schulenburg.
Published in journal: Nature Communications
Authors: Florian Buchholz, Lina M. Upterworth, Leif Tueffers, Espen E. Groth, Kira Haas, Daniel Schütz, Abigail Savietto Scholz, Aditi Batra, Surajit Pal, Samarpita Banerjee, Badri N. Dubey, Sören Franzenburg, Barbara Kalsdorf, Klaus F. Rabe, Dennis Nurjadi, Jan Rupp, Dan I. Andersson, Holger Sondermann, Marc Bramkamp, Roderich Roemhild, and Hinrich Schulenburg
Source/Credit: Kiel University
Edited by: Scientific Frontline
Reference Number: mcb052226_01
.jpg)