Biology subjects

Holmes, P.

Publications and source records attributed to Holmes, P..

3 recordsLinked to original sources

bioRxiv2026

Disruption of cAMP Signalling and RNA Regulation Confers Cefiderocol Resistance in Acinetobacter baumannii

Cefiderocol is a siderophore-conjugated cephalosporin used to treat severe multidrug-resistant Gram-negative infections. Its recent prioritisation for US national preparedness underscores its clinical importance, yet resistance can emerge despite apparent in vitro susceptibility. Here, we identify two regulatory routes to cefiderocol resistance in carbapenem-resistant Acinetobacter baumannii (CRAB): mutation of the cAMP-producing adenylate cyclase CavA and truncation of the glycine-rich RNA-binding domain of the post-transcriptional regulator Hfq. These variants occurred in contemporary clinical isolates, conferred resistance in a murine CRAB lung-infection model and imposed minimal fitness costs. In Escherichia coli, deletion of the CavA orthologue cyaA increased competitive fitness during sub-inhibitory cefiderocol exposure. Hfq-CLASH and integrated omics revealed Hfq-dependent regulation of Fur-associated iron homeostasis in A. baumannii. Under iron limitation, truncated-Hfq induced a defence-primed state that attenuated siderophore uptake and reduced cefiderocol activity. These findings identify bacterial regulatory state and iron availability as determinants of cefiderocol susceptibility, with implications for resistance surveillance and susceptibility testing.

microbiology↗

bioRxiv2023

Pathology of naturally acquired high pathogenicity avian influenza virus H5N1 infection in seabirds

The re-emergence of the high pathogenicity avian influenza virus (HPAIV) subtype H5N1 in the United Kingdom in 2021-2022 has caused unprecedented epizootic events in wild birds and poultry. During the summer of 2022 there was a shift in virus transmission dynamics resulting in increased HPAIV infection in seabirds and consequently a profound impact on seabird populations. To understand the pathological impact of HPAIV in seabirds, we have evaluated the virus distribution and associated pathological changes in the tissues of great skua (Stercorarius skua, n=8), long tailed skua (Stercorarius longicaudus, n=1), European herring gull (Larus argentatus, n=5), and black-headed gull (Chroicocephalus ridibundus, n=4). Grossly there was gizzard ulceration in one great skua and pancreatic necrosis in four herring gulls, which were confirmed for virus infection in situ by immunohistochemistry. Microscopical analysis revealed neuro-, pneumo-, lymphoidand cardiotropism of HPAIV H5N1, with the most common virus-associated pathological changes being pancreatic and splenic necrosis. Examination of the reproductive tract of the great skua revealed HPAIV-associated oophoritis and salpingitis, and virus replication within the oviductal epithelium. Across the birds, epitheliotropism was evident in the intestine, nasal turbinate, and trachea. This was, in contrast, not observed in the 2021 summer mortality event in great skuas and may be significant for the disease epidemiology observed in 2022. The emergence of HPAIV in seabirds, particularly during summer 2022, has challenged the dogma of HPAIV dynamics, posing a significant threat to wild bird life with potential implications to the reproductive performance of seabirds of conservation importance.

pathology↗

bioRxiv2019

Pal stabilises the bacterial outer membrane during constriction by a mobilisation-and-capture mechanism

Coordination of outer membrane constriction with septation is critical to faithful division in Gram-negative bacteria and vital to the barrier function of the membrane. Recent studies suggest this coordination is through the active accumulation of the peptidoglycan-binding outer membrane lipoprotein Pal at division sites by the Tol system, but the mechanism is unknown. Here, we show that Pal accumulation at Escherichia coli division sites is a consequence of three key functions of the Tol system. First, Tol mobilises Pal molecules in dividing cells, which otherwise diffuse very slowly due to their binding of the cell wall. Second, Tol actively captures mobilised Pal molecules and deposits them at the division septum. Third, the active capture mechanism is analogous to that used by the inner membrane protein TonB to dislodge the plug domains of outer membrane TonB-dependent nutrient transporters. We conclude that outer membrane constriction is coordinated with cell division by active mobilisation-and-capture of Pal at division septa by the Tol system.

microbiology↗