Biology subjects

Quinlan, M.

Publications and source records attributed to Quinlan, M..

4 recordsLinked to original sources

bioRxiv2025

Sphingosine synergizes with polymyxin antibiotics to kill Gram-negative bacteria

Antimicrobial resistance is an increasing threat to global health. However, there is a limited set of antibiotics that are effective against drug-resistant Gram-negative bacteria like Pseudomonas aeruginosa. One strategy to enhance the efficacy and longevity of existing antibiotics is by combining them with non-traditional antimicrobial adjuvants. Here, we examined if the host-derived antimicrobial lipid sphingosine could enhance the efficacy of a panel of antibiotics against P. aeruginosa in vitro. We found that sphingosine displayed strong synergy with the polymyxin antibiotics, polymyxin B and colistin, to inhibit growth of and kill P. aeruginosa, but did not significantly alter the efficacy of other tested antibiotic classes. The addition of sphingosine reduced the MIC of polymyxin B and colistin from 0.5 {micro}g/mL to 0.031 {micro}g/mL and 8 {micro}g/mL to 0.5 {micro}g/mL, respectively. This combination of sphingosine and polymyxin B synergized to inhibit the growth and survival of Klebsiella pneumoniae as well. In addition to sphingosine, we found that the sphingoid bases sphinganine (dihydrosphingosine) and phytosphingosine also enhanced the activity of polymyxins. Overall, these findings demonstrate that sphingosine is a potent adjuvant for polymyxins, and that the sphingosine- polymyxin combination is capable of killing P. aeruginosa and K. pneumoniae while using relatively low concentrations of polymyxin. This study may help in the development of new antimicrobial therapies for the treatment of Gram-negative bacterial infections. ImportanceAntibiotic resistance is an increasing threat to global health and there is a dire need to develop new therapies to treat multidrug-resistant infections. Here we show that sphingosine, a eukaryotic-derived antimicrobial lipid, synergizes with polymyxin antibiotics to inhibit the growth and survival of the Gram- negative bacteria, P. aeruginosa and K. pneumoniae. Thus, sphingosine has potential as an antimicrobial adjuvant for combinatorial therapies with polymyxins to treat Gram-negative infections.

microbiology↗

bioRxiv2023

Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses

Viruses acquire host genes via horizontal gene transfer and can express them to manipulate host biology during infections. Some viral and host homologs retain sequence identity, but evolutionary divergence can obscure host origins. We used structural modeling to compare vaccinia virus proteins with metazoan proteomes. We identified vaccinia A47L as a homolog of gasdermins, the executioners of pyroptosis. An X-ray crystal structure of A47 confirmed this homology and cell-based assays revealed that A47 inhibits pyroptosis. We also identified vaccinia C1L as the product of a cryptic gene fusion event coupling a Bcl-2 related fold with a pyrin domain. C1 associates with components of the inflammasome, a cytosolic innate immune sensor involved in pyroptosis, yet paradoxically enhances inflammasome activity, suggesting a benefit to poxvirus replication in some circumstances. Our findings demonstrate the potential of structural homology screens to reveal genes that viruses capture from hosts and repurpose to benefit viral fitness.

evolutionary biology↗

bioRxiv2022

The actin nucleator Spire cooperates with Rab11 to initiate nascent dendrite branches.

Dendrites form arbors whose size, shape and complexity define how neurons cover their receptive territories. Actin dynamics contribute to growth and remodeling of dendrite arbors. Here we examined how Spire, a conserved actin nucleation factor, promotes formation of new branches in vivo. In live imaging of Drosophila class IV dendritic arborization (c4da) neurons, Spire was observed at new sites of branch initiation, where it assembled new actin polymer in a burst just prior to filopodial outgrowth. For dendrite arborization, Spire required intact structural domains to nucleate actin and target the secretory network, and interacted with Rab11 GTPase, a key regulator of recycling endosomes. Together, these findings support a model in which Spire cooperates with Rab11 to promote new dendrite branches by linking localized actin dynamics with intracellular trafficking of endosomes that deliver lipids and cargoes to fuel protrusive outgrowth of nascent dendrites.

neuroscience↗

bioRxiv2019

Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study

Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. 31 participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d=0.89; p=0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d=0.86-1.08; all p-values <0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p>0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.

physiology↗