Biology subjects

Douglas, E.

Publications and source records attributed to Douglas, E..

4 recordsLinked to original sources

bioRxiv2026

Commonly prescribed medicines antagonise anti-MRSA antibiotics and select for resistance

Many commonly prescribed non-antibiotic medicines have off-target antimicrobial activity, yet their impact on antibiotic efficacy remains poorly understood. In this study, we investigated eight widely used UK prescription medicines and identified simvastatin, amlodipine, and fluoxetine as growth inhibitory towards methicillin-resistant Staphylococcus aureus (MRSA). These drugs disrupt bacterial membranes, with amlodipine and fluoxetine also triggering stress responses linked to cell wall and membrane damage. Further mechanistic analysis using transposon mutant screening revealed that simvastatin impairs cell wall synthesis by inhibiting the mevalonate pathway. Notably, checkerboard assays demonstrated antagonistic interactions: simvastatin reduced the efficacy of {beta}-lactams and vancomycin, amlodipine with vancomycin and daptomycin, and fluoxetine with vancomycin activity. Prolonged exposure to these drugs also accelerated resistance development to vancomycin and daptomycin. Together, these findings underscore the potential for commonly prescribed non-antibiotic medicines to undermine antibiotic therapy, warranting further study given the rising S. aureus treatment failures.

microbiology↗

bioRxiv2022

Prefrontal cortex melanocortin 4 receptors (MC4R) mediate food intake behavior in mice

BackgroundMelanocortin 4 receptor (MC4R) activity in the hypothalamus is crucial for regulation of metabolism and food intake. The peptide ligands for the MC4R are associated with feeding, energy expenditure, and also with complex behaviors that orchestrate energy intake and expenditure, but the downstream neuroanatomical and neurochemical targets associated with these behaviors are elusive. In addition to strong expression in the hypothalamus, the MC4R is highly expressed in the medial prefrontal cortex, a region involved in executive function and decision-making. MethodsUsing viral techniques in genetically modified mice combined with molecular techniques, we identify and describe the neuronal dynamics, and define the effects on feeding behavior of a novel population of MC4R expressing neurons in the infralimbic region of the cortex. ResultsHere, we describe a novel population of MC4R-expressing neurons in the infralimbic (IL) region of the mouse prefrontal cortex that are glutamatergic, receive input from melanocortinergic neurons of the arcuate hypothalamus, and project to multiple regions that coordinate appetitive responses to food-related stimuli. The neurons are depolarized by application of MC4R-specific peptidergic agonist, THIQ. Deletion of MC4R from the IL neurons causes increased food intake and body weight gain and impaired executive function in simple food-related behavior tasks. ConclusionTogether, these data suggest that MC4R neurons of the IL play a critical role in the regulation of food intake.

neuroscience↗

bioRxiv2021

Self-sensitisation of Staphylococcus aureus to the antimicrobial factors found in human blood.

Introductory ParagraphFor opportunistic pathogens, the switch from a commensal to an invasive lifestyle is often considered an accidental event. But with plentiful opportunity, what leads one accidental event to result in an invasive infection, and another not to? And how much of this apparent stochasticity is driven by bacterial factors? To answer these questions, here we focussed on the major human pathogen Staphylococcus aureus, which can both reside asymptomatically as a member of our respiratory microbiome, or become invasive and cause infections as severe as bacteraemia. Survival upon exposure to the antibacterial factors found in serum is a critical aspect of their ability to cause bacteraemia, and across a collection of 300 clinical isolates we found there to be significant variability in this capability. Utilising a GWAS approach we have uncovered the genetic basis of much of this variability through the identification and functional verification of a number of new polymorphic loci that affect serum survival: tcaA, tarK, gntR, ilvC, arsB, yfhO, and pdhD. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, while simultaneously enhancing the sensitivity of S. aureus to serum through a process involving the ligation of wall teichoic acids into the cell wall. As blood-stage infections are a transmission dead-end for the bacteria, that S. aureus actively responds to serum to produce a protein which specifically limits their ability to survive in this environment demonstrates that the switch from the commensal to the invasive lifestyle is complex, and that TcaA may contribute to the long-term success of S. aureus by restricting the bacteria to their more readily transmissible commensal state.

microbiology↗

bioRxiv2020

Resistance to Ceftazidime/Avibactam Plus Meropenem/Vaborbactam When Both are Used Together Achieved in Four Steps From Metallo-β-Lactamase Negative Klebsiella pneumoniae.

Serine cephalosporinases and carbapenemases are dominant causes of critically important {beta}-lactam resistance in Klebsiella pneumoniae. This has led to the recent clinical deployment of new serine {beta}-lactamase inhibitors used in combination with {beta}-lactams. Starting with clinical K. pneumoniae isolates and adding plasmids carrying the OXA-48-like class D carbapenemase, OXA-232, the class A carbapenemase KPC-3, the class A cephalosporinase CTX-M-14 and mutant derivatives of these enzymes, we set out to identify the steps required to give resistance to the recently approved {beta}-lactam/{beta}-lactamase inhibitor pairs ceftazidime/avibactam and meropenem/vaborbactam when both are used together. We show that four steps: ompK36 and ramR loss-of-function plus carriage of OXA-232 and KPC-3-D178Y, all of which have been observed in clinical isolates, allow K. pneumoniae to resist the combined use of both {beta}-lactam/{beta}-lactamase inhibitor pairs. These findings have implications for decision making about sequential and combinatorial use of {beta}-lactam/{beta}-lactamase inhibitor pairs to treat K. pneumoniae infections, and suggest simple surveillance activities that might identify intermediate stages in resistance acquisition and therefore guide therapy to reduce the emergence of dual resistant strains.

microbiology↗