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UK funding (£562,114): Alteration in bacterial cell envelope structure as the mechanism of antibiotic resistance and cell death Ukri1 Dec 2024 UK Research and Innovation, United Kingdom
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Alteration in bacterial cell envelope structure as the mechanism of antibiotic resistance and cell death
| Abstract | Antibiotic resistance is one of the major threats to human health with an estimated cost of $1 trillion by 2050 if not effectively combatted. Just in 2019, antibiotic resistant bacteria killed more people than HIV/AIDS or malaria. Addressing this global problem requires a better fundamental understanding of how bacteria respond to environmental stress on the single-cell level and how antibiotics ultimately kill bacterial cells. For simple organisms such as bacteria, cell shape and size are crucial for growth, nutrient uptake, and motility. However, the biophysical and molecular mechanisms of how bacteria control their biomechanics and morphology to readily adapt to stress conditions such as antibiotics, are still unknown. Despite the traditional view, bacterial cells have highly plastic cell shapes and can dynamically transform their sizes to access more nutrients to optimise their growth. For example, in nutrient-poor conditions, bacteria increase cell surface area to volume ratio (S/V) to increase nutrient flux and effectively increase intracellular nutrient concentration. Also, when bacterial cells are exposed to stress conditions such as antibiotics, a decrease in S/V provides a beneficial cell shape transformation for reducing intercellular antibiotic concentration and lowering the damaging effect of antibiotics. Therefore, bacterial cell shape and size transformation represent a novel antibiotic-resistant pathway that facilitates bacterial adaptation to antibiotic treatments - requiring our immediate attention. However, how bacteria dynamically harness their morphology with antibiotic perturbations to optimise growth and proliferation is still an open question. Furthermore, how bacteria regulate their nano-scale molecular machinery to achieve robust morphological transformations under extreme osmotic pressures remains also unknown. This proposal focuses on developing novel experimental, multi-scale computational and theoretical approaches to better understand how bacteria control their shape and size under antibiotic stress and how antibiotics disrupt bacterial cell biomechanics ultimately causing bacterial cell death. One of the main hypotheses of this proposal is that when bacteria are exposed to high antibiotic concentrations, bacterial cell death originates in the unbalanced volume and surface area synthesis. Using single-cell imaging and image analysis we will extract bacterial drastic cell shape and size transformations during antibiotic exposure - directly monitoring unbalanced bacterial growth responsible for deadly cell lysis. Drug candidates that effectively induce unbalanced growth will be supplemented with highly effective DNA-targeting antibiotics formulating effective antibiotic cocktails. Therefore, in this proposal we seek synergistic drug combinations to optimise treatment protocols to effectively kill bacterial cells. To understand how bacteria change their shape and size on the molecular level, we will develop molecular dynamics simulations of bacterial cell envelope that will identify relevant molecular players responsible for robust cell-shape control. This computational model will reveal molecular mechanisms behind unbalanced growth and how bacteria control their S/V ratio at the nano-scale level. By combining experimental and computational approaches, we will develop a research framework to prevent the emergence of antibiotic resistance mediated by bacterial cell shape transformations. Therefore, this research will address the urgent and timely problem of antibiotic resistance and will reveal how disruption of biophysical and biochemical pathways induce bacterial cell death, revealing basic design principles for the development of new antibiotic treatments and adjuvant therapies. |
| Category | Research Grant |
| Reference | BB/Y009002/1 |
| Status | Active |
| Funded period start | 01/12/2024 |
| Funded period end | 30/11/2027 |
| Funded value | £562,114.00 |
| Source | https://gtr.ukri.org/projects?ref=BB%2FY009002%2F1 |
Participating Organisations
| Queen Mary University of London |
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: Queen Mary University of London, London.
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