Recent publications describe multiple independent research efforts aimed at countering antibiotic resistance in bacteria. These studies, conducted by separate teams, explore different vulnerabilities in bacterial survival mechanisms, including protein-folding systems, efflux pumps, and immunity to bacteriophages.
Targeting Protein-Folding Systems to Disable Resistance and Cross-Protection
Study Overview
A study published in the journal eLife describes a mechanism that can disable antibiotic resistance in bacteria and disrupt a process called cross-protection.
- Cross-protection occurs when resistant bacteria degrade antibiotics in their environment, lowering drug concentrations and allowing nearby susceptible bacteria to survive.
The research focused on synthetic polymicrobial communities of Pseudomonas aeruginosa and Stenotrophomonas maltophilia, which are relevant to cystic fibrosis lung infections. S. maltophilia is highly resistant to antibiotics, including β-lactams, primarily through the production of β-lactamase enzymes.
Research Methodology
Researchers targeted a protein-folding system essential for the function of bacterial resistance enzymes. Two strategies were tested:
- Genetic deletion of a protein-folding gene
- Chemical inhibition of the system
Both methods deactivated resistance enzymes and sensitized the bacteria to β-lactam antibiotics. Experiments in wax moth larvae and mixed bacterial communities showed that disrupting the folding system prevented one bacterial species from protecting another.
Background
P. aeruginosa is the most prevalent organism in cystic fibrosis lung infections and is treated with β-lactam antibiotics. S. maltophilia is increasingly detected in cystic fibrosis microbiomes and is resistant to nearly all antibiotics, including β-lactams. Cross-protection has been shown experimentally to promote the evolution of β-lactam-resistant P. aeruginosa strains.
Research Team and Funding
The study was led by Nikol Kadeřábková of The University of Texas at Austin and Chris Furniss of Imperial College London.
- Kadeřábková is a research associate in the lab of Despoina Mavridou at UT Austin's Department of Molecular Biosciences.
- Furniss is a postdoctoral research fellow at Imperial College London.
Funding was provided by the U.S. National Institute of Allergy and Infectious Diseases, the U.K. Medical Research Council, the Cockrell School of Engineering, the Fundação para a Ciência e a Tecnologia, I.P., the Welch Foundation, and the U.K. Biotechnology and Biological Sciences Research Council.
The findings may inform the treatment of a range of antibiotic-resistant infections due to similar bacterial survival mechanisms found across many species.
Redesigning Antibiotics to Overcome Efflux Pump Resistance
A separate study led by King's College London and published in the Journal of Medicinal Chemistry describes an approach called "Efflux Resistance Breaker" (ERB) that aims to overcome bacterial efflux pump resistance.
The team demonstrated that antibiotics can be chemically redesigned to be less susceptible to removal by efflux pumps, allowing higher concentrations to remain inside bacterial cells. The approach builds resistance-breaking properties directly into the antibiotic molecule, unlike previous strategies that combined antibiotics with separate efflux pump inhibitors.
Chemical Inhibition of Bacterial Immunity Against Bacteriophages
Research Context
The Gerdt Lab at Indiana University Bloomington conducts research to understand how to weaken bacteria's defenses against viruses. Antimicrobial resistance (AMR), where bacteria and fungi develop defenses against drugs designed to eliminate them, represents a critical global public health concern, as stated by the Centers for Disease Control and Prevention.
Bacteriophages as an Alternative
Bacteriophages, which are viruses that infect and kill bacteria, offer a potential alternative to antibiotics. Unlike antibiotics, which can target both pathogenic and beneficial bacteria, bacteriophages can be used more precisely to eliminate specific problematic bacterial strains, leaving advantageous microbes unaffected. This targeted approach also has applications in agriculture.
However, bacteria can develop immunity to bacteriophages, similar to how they develop antibiotic resistance.
Key Discovery
Former lab member Zhiyu Zang, now a post-doctoral candidate at the Swiss Federal Technology Institute of Lausanne, discovered a chemical molecule that, when combined with a bacteriophage, assists the virus in overcoming a bacterium's immune response.
This discovery was detailed in the paper "Chemical inhibition of a bacterial immune system," co-authored by Zang and J.P. Gerdt, and published in Cell Host and Microbe.
Significance and Applications
Zang stated that the study is significant for identifying the first small molecule capable of inhibiting a bacterial immune system. The immune system under investigation is present in approximately 2,000 different bacterial species, including common antibiotic-resistant pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus, which cause many hospital-acquired infections.
While antibiotics are expected to remain the primary treatment for human bacterial infections, the Gerdt Lab's findings may be applicable to difficult-to-treat human infections and in sectors like agriculture, where antibiotic overuse contributes to the spread of resistance.
The lab's long-term objective is to develop a collection of inhibitors for various bacteria, a process Gerdt anticipates could take 10 to 15 years. Undergraduate students, including Olivia Duncan, contributed to identifying molecules that chemically inhibited the bacterium's immune system.