Biology subjects

Perrier, S.

Publications and source records attributed to Perrier, S..

6 recordsLinked to original sources

bioRxiv2026

Targeting intracellular mycobacteria using novel antibiotic-loaded nanoparticles

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge. Currently treatment of drug-sensitive TB, involves a six-month regimen consisting of a combination of four anti-TB drugs, with drug-resistant TB requiring over two years of treatment and additional drugs. As toxicity of anti-TB drugs often leads to poor compliance, disease relapse and the emergence of drug-resistant strains, new strategies to reduce drug toxicity and shorten treatment duration are critical. We report nanocarrier-based drug delivery systems targeting macrophages, which primarily support replication and survival of Mtb. We have developed mannose-functionalized nanoparticles that bind to mannose receptors on macrophages and feature a pH-sensitive core which releases an encapsulated drug in the acidic lysosomal environment of macrophages. Rifampicin (RIF), a main anti-TB drug currently in use clinically, was encapsulated within the nanoparticles. We demonstrate that antibiotic-containing nanocarriers efficiently accumulated in macrophages without causing toxicity. Encapsulated RIF showed enhanced efficacy against both BCG and Mtb in primary macrophages. Biodistribution studies in mice revealed that the nanoparticles have extended circulation time and do not induce toxicity. In addition, the encapsulated RIF showed better targeting of mycobacteria when compared to free RIF in a murine model of mycobacterial infection. Such an enhanced bacterial killing using mannose-functionalised nanocarriers loaded with the key anti-TB drug rifampicin offers excellent potential for TB therapy.

microbiology↗

bioRxiv2025

Machine learning assisted classification of cell and brain penetrating peptides

Crossing the blood-brain barrier (BBB) remains a major obstacle for central nervous system therapeutics. Short peptides have emerged as promising vectors, including cell-penetrating peptides (CPPs) and brain-penetrating peptides (BPPs). However, the structural and physicochemical features that distinguish CPPs from BPPs remain poorly understood, limiting rational design. Here, we compiled a curated dataset of 490 peptides, encompassing CPPs, BPPs, and non-BPP controls, and systematically analysed their amino acid composition, sequence distribution, and physicochemical descriptors. BPPs were found to exhibit a more balanced distribution of cationic, polar, and hydrophobic residues compared to CPPs, which were enriched in contiguous arginine and lysine blocks. Physicochemical analysis revealed that BPPs had lower charge density, greater stability, and reduced aromaticity relative to CPPs. Dimensionality reduction confirmed BPPs occupy an intermediate chemical space between CPPs and non-BPPs. Machine learning classification, particularly with Extra Trees models, achieved strong performance in discriminating peptide classes, with charge, instability index, and aromaticity identified as the most predictive features. These findings suggest that BBB penetration is not a simple extension of cell penetration but requires finely tuned physicochemical properties. This study provides mechanistic insights into BPP design and highlights machine learning as a valuable tool for engineering next-generation BBB-penetrating peptides and peptide-mimetic materials.

cell biology↗

bioRxiv2025

Potentials of Machine Learning in Predicting Key Features of Synthetic Antimicrobial Polymers (SAMPs)

The widespread antimicrobial resistance urged the need for novel antimicrobial agents. Synthetic antimicrobial polymers (SAMPs) were proposed as promising antibiotics to overcome the drawbacks of host-defence peptides. A machine learning forecast can be beneficial to evaluate the influence of SAMPs features on their potency and toxicity. In this study, we utilised a library of 20 polyacrylamides varied in: 1) type of amine side chain, 2) chain length, 3) cationic amine ratio, and 4) polymer architecture. Their structure-activity relationship was evaluated by comparing experimental observations and machine learning models. While classification models showed good fit in the training set, regression models demonstrated better fit in the testing set. Regression random forest and gradient boosting methods demonstrated reliable reproducibility of feature importance and maintained the tree structure throughout multiple runs. Beeswarm and waterfall plots provided an overview of the joint SHapley Additive exPlanations (SHAP) values of features on a specific data point. Based on validation tests and the consistency of feature importance and SHAP values, we conclude that boosting-ensemble methods can be utilized in forecasting future SAMPs.

microbiology↗

bioRxiv2025

Cationic antimicrobial copolymers reveal immunomodulatory properties in LPS stimulated macrophages in vitro

Antimicrobial polymers, which have emerged as a promising alternative to antibiotics in the fight against antimicrobial resistance, are based on the design of cationic host defence peptides (CHDPs). Being a part of the mammalian innate immune system, CHDPs possess both antimicrobial and immunoregulatory effects to manage bacterial infections. However, the immunomodulatory effects of antimicrobial polymers remain largely unexplored. Within this work, a library of 15 copolymers were synthesised by reversible addition-fragmentation chain transfer (RAFT) polymerisation and their abilities to modulate pro-inflammatory pathways in LPS-activated murine and human macrophages were investigated. We found that two diblock copolymers with cationic units copolymerised with either apolar or hydrophilic comonomers appeared to have anti-inflammatory activity through suppression of the activation of the NF-{kappa}B signalling pathway, scavenging of reactive oxygen species and reduced production of the pro-inflammatory cytokine IL-6. Furthermore, the cationic-apolar copolymer exhibits significant antimicrobial activity against P. aeruginosa. Thus, this promising copolymer holds potential as a dual-action therapeutic, effectively combating bacterial infections while curbing prolonged inflammation and thereby preventing sepsis at the site of infection.

microbiology↗

bioRxiv2023

The staphylococcal type VII secretion system impacts daptomycin sensitivity through controlling bacterial cell envelope integrity

The human pathogen Staphylococcus aureus encodes a specialised type VII secretion system (T7SS), which plays an important role in bacterial virulence during infection. However, the functions the T7SS during infection and in bacterial physiology remain unclear. Here we demonstrate that S. aureus strains lacking the the T7SS effector EsxC ({Delta}esxC) was highly sensitive to the important last resort drug, daptomycin, as well as other membrane-targeting antibiotics, including gramicidin and bithionol. To understand how EsxC mediates increased antibiotic sensitivity, we investigated its functions in the staphylococcal cell envelope. Scanning electron microscopy analysis of an esxC mutant revealed a distinct cell surface morphology. Interestingly, {Delta}esxC displayed a decrease in membrane fluidity, altered membrane protein profiles and altered cell wall synthesis. The esxC mutant demonstrated enhanced daptomycin binding which correlated with the increased negative charge of mutant membranes. Calcium ions, which can bind membranes affecting charge, impacted growth of {Delta}esxC and sensitivity to daptomycin, suggesting that EsxC may modulate calcium binding to membranes. Furthermore, the esxC mutant displayed a heightened susceptibility to daptomycin during intracellular infection, and in a murine skin infection model. Thus, our data show that the T7SS effector EsxC impacts sensitivity of S. aureus to membrane-acting drugs such as daptomycin through modulation of cell membrane integrity, indicating its potential as a drug target. Author SummaryT7SS has a range of functions in bacteria including specific roles in bacterial physiology including DNA uptake, membrane integrity and bacterial development. In S. aureus T7SS has been shown to be critical for bacterial virulence, intra-species competition and in host cell interactions, although their functions in bacterial physiology are not clear. Here we report a role of the staphylococcal T7SS effector EsxC in the modulation of the cell membrane and surface integrity, which impacts the activity of membrane targeting drugs like daptomycin. Our data indicate that targeting this system could potentially enhance activity of existing therapeutic agents.

microbiology↗

bioRxiv2019

The type VII secretion system protects Staphylococcus aureus against antimicrobial host fatty acids

The Staphylococcus aureus type VII secretion system (T7SS) exports several proteins that are pivotal for bacterial virulence. The mechanisms underlying T7SS-mediated staphylococcal survival during infection nevertheless remain unclear. Here we show that the absence of EsxC, a small secreted effector implicated in bacterial persistence, results in cell membrane defects in S. aureus. Interestingly, isogenic mutants lacking EsxC, other T7SS effectors EsxA and EsxB, or the membrane-bound ATPase EssC, are more sensitive to killing by the host-derived antimicrobial fatty acid, linoleic acid (LA), compared to the wild-type (WT). LA induces more cell membrane damage in the T7SS mutants compared to the WT. Although WT and mutant strains did not differ in their ability to bind labelled LA, membrane lipid profiles show that T7SS mutants are less able to incorporate LA into their membrane phospholipids. Furthermore, proteomic analyses of WT and mutant cell fractions reveal that, in addition to compromising membranes, T7SS defects induce oxidative stress and hamper their response to LA challenge. Thus, our findings indicate that T7SS is crucial for S. aureus membrane integrity and homeostasis, which is critical when bacteria encounter antimicrobial fatty acids.

microbiology↗