Protein aggregation as an antibiotic design strategy.

Taking advantage of the xenobiotic nature of bacterial infections, we tested whether the cytotoxicity of protein aggregation can be targeted to bacterial pathogens without affecting their mammalian hosts. In particular, we examined if peptides encoding aggregation-prone sequence segments of bacterial proteins can display antimicrobial activity by initiating toxic protein aggregation in bacteria, but not in mammalian cells. Unbiased in vitro screening of aggregating peptide sequences from bacterial genomes lead to the identification of several peptides that are strongly bactericidal against methicillin-resistant Staphylococcus aureus. Upon parenteral administration in vivo, the peptides cured mice from bacterial sepsis without apparent toxic side effects as judged from histological and hematological evaluation. We found that the peptides enter and accumulate in the bacterial cytosol where they cause aggregation of bacterial polypeptides. Although the precise chain of events that leads to cell death remains to be elucidated, the ability to tap into aggregation-prone sequences of bacterial proteomes to elicit antimicrobial activity represents a rich and unexplored chemical space to be mined in search of novel therapeutic strategies to fight infectious diseases.

Protein aggregation in bacteria: the thin boundary between functionality and toxicity.

Misfolding and aggregation of proteins have a negative impact on all living organisms. In recent years, aggregation has been studied in detail due to its involvement in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, and type II diabetes--all associated with accumulation of amyloid fibrils. This research highlighted the central importance of protein homeostasis, or proteostasis for short, defined as the cellular state in which the proteome is both stable and functional. It implicates an equilibrium between synthesis, folding, trafficking, aggregation, disaggregation and degradation. In accordance with the eukaryotic systems, it has been documented that protein aggregation also reduces fitness of bacterial cells, but although our understanding of the cellular protein quality control systems is perhaps most detailed in bacteria, the use of bacterial proteostasis as a drug target remains little explored. Here we describe protein aggregation as a normal physiological process and its role in bacterial virulence and we shed light on how bacteria defend themselves against the toxic threat of aggregates. We review the impact of aggregates on bacterial viability and look at the ways that bacteria use to maintain a balance between aggregation and functionality. The proteostasis in bacteria can be interrupted via overexpression of proteins, certain antibiotics such as aminoglycosides, as well as antimicrobial peptides--all leading to loss of cell viability. Therefore intracellular protein aggregation and disruption of proteostatic balance in bacteria open up another strategy that should be explored towards the discovery of new antimicrobials.

The Epidemiology of Chickenpox in England, 2016-2022: An Observational Study Using General Practitioner Consultations.

Chickenpox is a common childhood disease caused by varicella-zoster virus (VZV). VZV vaccination is not part of the UK childhood immunisation programme, but its potential inclusion is regularly assessed. It is therefore important to understand the ongoing burden of VZV in the community to inform vaccine policy decisions. General practitioner (GP) chickenpox consultations were studied from 1 September 2016 to 9 December 2022. Over the study period, the mean weekly chickenpox consultation rate per 100,000 population in England was 3.4, with a regular peak occurring between weeks 13 and 15. Overall, rates decreased over time, from a mean weekly rate of 5.5 in 2017 to 4.2 in 2019. The highest mean weekly rates were among children aged 1-4 years. There was no typical epidemic peak during the COVID-19 pandemic, but in 2022, rates were proportionally higher among children aged < 1 year old compared to pre-pandemic years. Chickenpox GP consultation rates decreased in England, continuing a longer-term decline in the community. The COVID-19 pandemic impacted rates, likely caused by the introduction of non-pharmaceutical interventions to prevent SARS-CoV-2 transmission. The lasting impact of the interruption of typical disease transmission remains to be seen, but it is important to monitor the chickenpox burden to inform decisions on vaccine programmes.

The importance of the glycosylation of antimicrobial peptides: natural and synthetic approaches.

Glycosylation is one of the most prevalent post-translational modifications of a protein, with a defining impact on its structure and function. Many of the proteins involved in the innate or adaptive immune response, including cytokines, chemokines, and antimicrobial peptides (AMPs), are glycosylated, contributing to their myriad activities. The current availability of synthetic coupling and glycoengineering technology makes it possible to customise the most beneficial glycan modifications for improved AMP stability, microbicidal potency, pathogen specificity, tissue or cell targeting, and immunomodulation.