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Morley, V. J.

Publications and source records attributed to Morley, V. J..

4 recordsLinked to original sources

Genetic shifts in viral populations: how sudden vs gradual changes in host species composition affect the stability and dynamics of genetic variability in viral populations

Sudden and gradual changes in host species composition --transitioning from more permissive to less permissive hosts-- have been shown to influence viral fitness, virulence, and rates of molecular evolution. In this study, we analyzed the roles of stochasticity and selection using previously published time-series data from evolving populations of Sindbis virus under different rates of host replacement. First, an approximate Markov model within the Wright-Fisher diffusion framework revealed a reduction in effective population size by approximately half in scenarios involving sudden host changes. These scenarios were also associated with fewer and generally weaker beneficial mutations. Second, genetic distance analysis between populations at consecutive time points indicated that populations undergoing gradual host changes evolved steadily until the original host was no longer present. Distances to the ancestral sequence in these cases exhibited occasional leapfrog phenomena, where the rise of certain haplotypes is not predictable based solely on their relatedness to previously dominant ones. In contrast, populations exposed to sudden host changes displayed less stable compositions and diverged from the ancestral sequence at a more constant rate. Third, we observed that allele frequencies distribution followed a power law consistent with Taylors law. Both treatments exhibited high levels of allele aggregation with significant fluctuations, where neutral, beneficial, and deleterious alleles could be distinguished by their general behavior and their position on Taylors plot. Finally, we found evidence that the host replacement regime influences the temporal distribution of mutations across the genome.

evolutionary biology↗

Ion exchange biomaterials to capture daptomycin and prevent resistance evolution in off-target bacterial populations

Daptomycin (DAP), a cyclic anionic lipopeptide antibiotic, is among the last resorts to treat multidrug resistant (vancomycin resistant Enterococcus faecium or methicillin resistant Staphylococcus aureus) Gram-positive bacterial infections. DAP is administered intravenously and biliary excretion results in the introduction of DAP ([~]5-10 % of the intravenous DAP dose) arriving in the gastrointestinal (GI) tract where it drives resistance evolution in off-target populations of Enterococcus faecium bacteria. Previously, we have shown that the oral administration of cholestyramine, an ion exchange biomaterial (IXB) sorbent, prevents DAP treatment from enriching DAP-resistance in populations of E. faecium shed from mice. Here, we engineer the biomaterial-DAP interfacial interactions to uncover the antibiotic removal mechanisms. The IXB-mediated DAP capture from aqueous media was measured in both controlled pH/electrolyte solutions and in simulated intestinal fluid (SIF) to uncover the molecular and colloidal mechanisms of DAP removal from the GI tract. Our findings show that the IXB electrostatically adsorbs the anionic antibiotic via a time-dependent diffusion-controlled process. Unsteady-state diffusion-adsorption mass balance describes the dynamics of adsorption well, and the maximum removal capacity is beyond the electric charge stoichiometric ratio because of DAP self-assembly. This study may open new opportunities for optimizing cholestyramine adjuvant therapy to prevent DAP resistance, as well as designing novel biomaterials to remove off-target antibiotics from the GI tract. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/495716v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@ec034eorg.highwire.dtl.DTLVardef@cd1106org.highwire.dtl.DTLVardef@118dbcborg.highwire.dtl.DTLVardef@106287c_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

Oral cholestyramine prevents enrichment of diverse daptomycin-resistance mutations in intestinal Enterococcus faecium

Background and ObjectivesPreviously, we showed proof-of-concept in a mouse model that oral administration of cholestyramine prevented enrichment of daptomycin-resistant Enterococcus faecium in the gastrointestinal (GI) tract during daptomycin therapy. Cholestyramine binds daptomycin in the gut, which removes daptomycin selection pressure and so prevents the enrichment of resistant clones. Here, we investigated two open questions related to this approach: 1) can cholestyramine prevent the enrichment of diverse daptomycin mutations emerging de novo in the gut? 2) how does the timing of cholestyramine administration impact its ability to suppress resistance? MethodologyMice with GI E. faecium were treated with daptomycin with or without cholestyramine, and E. faecium was cultured from feces to measure changes in daptomycin susceptibility. A subset of clones was sequenced to investigate the genomic basis of daptomycin resistance. ResultsCholestyramine prevented the enrichment of diverse resistance mutations that emerged de novo in daptomycin-treated mice. Whole-genome sequencing revealed that resistance emerged through multiple genetic pathways, with most candidate resistance mutations observed in the clsA gene. Additionally, we observed that cholestyramine was most effective when administration started prior to the first dose of daptomycin. However, beginning cholestyramine after the first daptomycin dose reduced the frequency of resistant E. faecium compared to not using cholestyramine at all. Conclusions and ImplicationsCholestyramine prevented the enrichment of diverse daptomycin-resistance mutations in intestinal E. faecium populations during daptomycin treatment, and it is a promising tool for managing transmission of daptomycin-resistant E. faecium.

microbiology↗

An adjunctive therapy approach prevents antibiotic resistance emergence in opportunistic pathogens colonizing the gut

A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an anti-antibiotic to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.

evolutionary biology↗