Periodic Reporting for period 1 - PhotoLiB (Photoswitchable amphiphilic lipids: a photopharmacology strategy to combat drug-resistant bacterial infections.)
Période du rapport: 2021-07-01 au 2023-06-30
The research conducted in this fellowship has successfully addressed a critical issue in antibiotic development—the rapid adaptation of bacteria to external stresses, including antibiotics, and their ability to develop robust defense mechanisms. Our proposed solution involved a novel approach: targeting bacterial membranes and cell walls. Unlike modifiable proteins and enzymes, these structural elements resist alteration, leading to the effective elimination of bacteria.
In response to the escalating concern over antibiotic resistance, our research introduced an innovative strategy that combines photopharmacology principles with membrane-disrupting drugs. The core concept involved connecting cationic amphiphilic molecules with photoswitchable probes to modulate drug mobility and activity. This enhanced selectivity and accelerated bacterial membrane disruption.
The primary objectives of the research were successfully achieved: (1) developing new antibacterial drugs, Photoswitchable Amphiphilic Lipids (PALs), which interact with and disrupt bacterial membranes and cell walls upon light activation; (2) identifying PALs capable of disrupting bacterial membranes at different wavelengths, providing versatility; (3) exploring synergistic effects of PALs when combined with standard antibiotics to amplify antibiotic efficacy.
The compounds devised during the fellowship represent a unique approach where light serves as a modulator, employing a switch-on/off strategy to regulate their activity. This innovative mechanism enables the selective targeting of Gram-positive bacteria, minimizing exposure time and mitigating the risk of resistance development. The implications of this research point towards a groundbreaking strategy for the development of antibiotics with increased efficacy and reduced potential for resistance.
This research significantly aligns with the European research priority of "Antimicrobial Resistance," addressing a critical global health challenge. It transcends geographical boundaries and contributes to global public health, while also aligning with the objectives of European Health Systems and the interests of European industries. It establishes a crucial research foundation for innovative strategies and therapies against drug-resistant bacterial infections, enhancing healthcare practices, patient outcomes, and industry competitiveness.
In conclusion, this research goes beyond academia, offering real-world solutions aligned with European health priorities and the imperative for novel therapeutic strategies. The project has made a substantive and enduring contribution to the broader health landscape, particularly in the ongoing battle against antibiotic-resistant bacterial strains.
In response to the escalating concern over antibiotic resistance, our research introduced an innovative strategy that combines photopharmacology principles with membrane-disrupting drugs. The core concept involved connecting cationic amphiphilic molecules with photoswitchable probes to modulate drug mobility and activity. This enhanced selectivity and accelerated bacterial membrane disruption.
The primary objectives of the research were successfully achieved: (1) developing new antibacterial drugs, Photoswitchable Amphiphilic Lipids (PALs), which interact with and disrupt bacterial membranes and cell walls upon light activation; (2) identifying PALs capable of disrupting bacterial membranes at different wavelengths, providing versatility; (3) exploring synergistic effects of PALs when combined with standard antibiotics to amplify antibiotic efficacy.
The compounds devised during the fellowship represent a unique approach where light serves as a modulator, employing a switch-on/off strategy to regulate their activity. This innovative mechanism enables the selective targeting of Gram-positive bacteria, minimizing exposure time and mitigating the risk of resistance development. The implications of this research point towards a groundbreaking strategy for the development of antibiotics with increased efficacy and reduced potential for resistance.
This research significantly aligns with the European research priority of "Antimicrobial Resistance," addressing a critical global health challenge. It transcends geographical boundaries and contributes to global public health, while also aligning with the objectives of European Health Systems and the interests of European industries. It establishes a crucial research foundation for innovative strategies and therapies against drug-resistant bacterial infections, enhancing healthcare practices, patient outcomes, and industry competitiveness.
In conclusion, this research goes beyond academia, offering real-world solutions aligned with European health priorities and the imperative for novel therapeutic strategies. The project has made a substantive and enduring contribution to the broader health landscape, particularly in the ongoing battle against antibiotic-resistant bacterial strains.
In WP1, the researcher achieved the following milestones: (1) synthesizing synthetic intermediates, and (2) creating final photoswitchable compounds. Crafting these compounds posed a considerable challenge due to their unique combination of a lipophilic moiety and a polar head in a single molecule. The synthesis complexity was a primary challenge of this project, demanding an extended period to establish the correct procedures. The researcher also conducted comprehensive characterizations of photoswitchable compound isomerization, gaining valuable skills in organic chemistry. WP2 centered on microbiological aspects, diligently conducted by the researcher at the UK Health Security Agency and King's College London. Several months of the fellowship were dedicated to these microbiology experiments, expanding the researcher's skill set beyond their primary field. WP3 is ongoing with continued collaboration at King's College London. The researcher's secured UCL fellowship ensures active involvement in the project's progression and the completion of remaining experiments.
In addition, the researcher: (1) Gained extensive training in organic chemistry analytical techniques, including NMR, LCMS, and UV spectroscopy; (2) Facilitated a knowledge exchange, contributing strong medicinal chemistry and drug discovery expertise, while acquiring proficiency in organic synthesis, analytical chemistry, and microbiology through collaboration; (3) Actively managed the project by participating in scientific and non-scientific aspects, from executing experiments to scientific management; (4) Engaged in the financial management of the project, alongside the supervisor, ensuring efficient resource allocation; (5) Supervised master's students in drug discovery projects related to infectious diseases.
Overall, the project's results will be shared in a research paper co-authored primarily by the researcher, with valuable contributions from the supervisor and project collaborators.
In addition, the researcher: (1) Gained extensive training in organic chemistry analytical techniques, including NMR, LCMS, and UV spectroscopy; (2) Facilitated a knowledge exchange, contributing strong medicinal chemistry and drug discovery expertise, while acquiring proficiency in organic synthesis, analytical chemistry, and microbiology through collaboration; (3) Actively managed the project by participating in scientific and non-scientific aspects, from executing experiments to scientific management; (4) Engaged in the financial management of the project, alongside the supervisor, ensuring efficient resource allocation; (5) Supervised master's students in drug discovery projects related to infectious diseases.
Overall, the project's results will be shared in a research paper co-authored primarily by the researcher, with valuable contributions from the supervisor and project collaborators.
The research conducted in this fellowship stands at the forefront of antibiotic development, addressing an urgent global concern: the adaptability of bacteria to external pressures, including antibiotics, and their ability to develop robust defence mechanisms. This research introduces an innovative approach that holds the potential to revolutionize antibacterial strategies. By targeting bacterial membranes and cell walls, which are inherently resistant to modification, the project promises to effectively eliminate bacteria and overcome their adaptation mechanisms. Moreover, the amalgamation of photopharmacology principles with membrane-disrupting drugs, resulting in Photoswitchable Amphiphilic Lipids (PALs), presents a groundbreaking paradigm shift in antibiotic development. PALs, activated by light, can disrupt bacterial membranes at varying wavelengths, providing versatility in their application. This research's exceptional progress beyond the state of the art lies in its multifaceted approach to tackle antibiotic resistance comprehensively.
Anticipated results until the end of the project are the development of a new class of antibacterial drugs, PALs, which exhibited unprecedented effectiveness in disrupting bacterial membranes and cell walls, thus eradicating bacteria. These compounds are poised to outperform existing antibiotics. By expanding the scope of antibacterial agents and increasing their selectivity, this research is likely to have significant impacts on the landscape of antibiotic drug discovery. In essence, the outcomes of this project transcend academia and extend into practical solutions to address antibiotic-resistant bacterial strains. Furthermore, it carries important socio-economic implications, as the potential success of this research can lead to novel therapeutic strategies against drug-resistant infections, potentially revolutionizing healthcare. It offers a substantial contribution to the global fight against antibiotic resistance and promises to make a lasting impact on societal and economic aspects related to healthcare and pharmaceuticals.
Anticipated results until the end of the project are the development of a new class of antibacterial drugs, PALs, which exhibited unprecedented effectiveness in disrupting bacterial membranes and cell walls, thus eradicating bacteria. These compounds are poised to outperform existing antibiotics. By expanding the scope of antibacterial agents and increasing their selectivity, this research is likely to have significant impacts on the landscape of antibiotic drug discovery. In essence, the outcomes of this project transcend academia and extend into practical solutions to address antibiotic-resistant bacterial strains. Furthermore, it carries important socio-economic implications, as the potential success of this research can lead to novel therapeutic strategies against drug-resistant infections, potentially revolutionizing healthcare. It offers a substantial contribution to the global fight against antibiotic resistance and promises to make a lasting impact on societal and economic aspects related to healthcare and pharmaceuticals.