Biology subjects

Brown, S. P.

Publications and source records attributed to Brown, S. P..

6 recordsLinked to original sources

bioRxiv2018

Resistance diagnostics as a public health tool to combat antibiotic resistance: A model-based evaluation

Rapid point-of-care resistance diagnostics (POC-RD) are thought to be a key tool in the fight against antibiotic resistance. By tailoring drug choice to infection genotype, doctors can improve treatment efficacy while limiting costs of inappropriate antibiotic prescription. Here we combine epidemiological theory and data to assess the potential of POC-RD innovations in a public health context, as a means to limit or even reverse selection for antibiotic resistance. POC-RD can be used to impose a non-biological fitness cost on resistant strains, by triggering targeted interventions that reduce their opportunities for transmission. We assess this diagnostic-imposed fitness cost in the context of a spectrum of bacterial population biologies and POC-RD conditional strategies, and find that the expected impact varies from selection against resistance for obligate pathogens to marginal public health improvements for opportunistic pathogens with high bystander antibiotic exposure during asymptomatic carriage (e.g. the pneumococcus). We close by generalizing the notion of RD-informed strategies to incorporate both POC and carriage surveillance information, and illustrate that coupling transmission control interventions to the discovery of resistant strains in carriage can potentially select against resistance in a broad range of opportunistic pathogens.

epidemiology↗

bioRxiv2018

Combinatorial quorum sensing in Pseudomonas aeruginosa allows for novel cheating strategies

In the opportunistic pathogen Pseudomonas aeruginosa, quorum sensing (QS) is a social trait that is exploitable by non-cooperating cheats. Previously it has been shown that by linking QS to the production of both public and private goods, cheats can be prevented from invading populations of cooperators and this has been termed a metabolic incentive to cooperate. We hypothesized P. aeruginosa could evolve novel cheating strategies to circumvent private goods metabolism by rewiring its combinatorial response to two QS signals (3O-C12-HSL and C4-HSL). We performed a selection experiment that cycled P. aeruginosa between public and private goods growth media and evolved an isolate which rewired its control of cooperative protease expression from a synergistic (AND-gate) response to dual signal input, to a 3O-C12-HSL only response. We show that this isolate circumvents metabolic incentives to cooperate and acts as a combinatorial signaling cheat, with a higher fitness in competition with its ancestor. Our results show three important principles; first, combinatorial QS allows for diverse social strategies to emerge; second, that restrictions levied by private goods are not sufficient to explain the maintenance of cooperation in natural populations and third that modifying combinatorial QS responses could result in important physiological outcomes in bacterial populations.

microbiology↗

bioRxiv2017

Modified antibiotic adjuvant ratios can slow and steer the evolution of resistance: co-amoxiclav as a case study

As the spread of antibiotic resistance outstrips the introduction of new antibiotics, reusing existing antibiotics is increasingly important. One promising method is to combine antibiotics with synergistically acting adjuvants that inhibit resistance mechanisms, allowing drug killing. Here we use co-amoxiclav (a commonly used and clinically important drug combination of the {beta}-lactam antibiotic amoxicillin and the {beta}-lactamase inhibitor clavulanate) to ask whether treatment efficacy and resistance evolution can be decoupled via component dosing modifications.\n\nA simple mathematical model predicts that different ratios of these two drug components can produce distinct evolutionary responses despite similar initial levels of control. We test this hypothesis by selecting Escherichia coli with a plasmid encoded {beta}-lactamase (ESBL CTX-M-14), against different proportions of amoxicillin and clavulanate. Consistent with our theory, we found that while resistance evolved under all conditions, the component ratio influenced both the rate and mechanism of resistance evolution. Specifically, we found that the current clinical practice of high amoxicillin to clavulanate ratios resulted in the most rapid failure due to the evolution of gene dosing responses. Increased plasmid copy number allowed E. coli to increase {beta}-lactamase dosing and effectively titrate out the low quantities of clavulanate, restoring amoxicillin resistance. In contrast, we found high clavulanate ratios were more robust - plasmid copy number did not increase, although porin or efflux resistance mechanisms were found, as in all drug ratios. Our results indicate that by changing the ratio of adjuvant to antibiotic we can slow and steer the path of resistance evolution. We therefore suggest the use of increased clavulanate dosing regimens to slow the rate of resistance evolution.

microbiology↗

bioRxiv2017

Variation in neuronal activity state, axonal projection target, and position principally define the transcriptional identity of individual neocortical projection neurons.

Single-cell RNA sequencing technologies have generated the first catalogs of transcriptionally defined neuronal subtypes of the brain. However, the biologically informative cellular processes that contribute to neuronal subtype specification and transcriptional heterogeneity remain unclear. By comparing the gene expression profiles of single layer 6 corticothalamic neurons in somatosensory cortex, we show that transcriptional subtypes primarily reflect axonal projection pattern, laminar position within the cortex, and neuronal activity state. Pseudotemporal ordering of 1023 cellular responses to manipulation of sensory input demonstrates that changes in expression of activity-induced genes both reinforced cell-type identity and contributed to increased transcriptional heterogeneity within each cell type. This is due to cell-type specific biases in the choice of transcriptional states following manipulation of neuronal activity. These results reveal that axonal projection pattern, laminar position, and activity state define significant axes of variation that contribute both to the transcriptional identity of individual neurons and to the transcriptional heterogeneity within each neuronal subtype.

neuroscience↗

bioRxiv2017

Division of labor, bet hedging, and the evolution of mixed biofilm investment strategies

Bacterial cells, like many other organisms, face a tradeoff between longevity and fecundity. Planktonic cells are fast growing and fragile, while biofilm cells are often slower growing but stress resistant. Here we ask: why do bacterial lineages invest simultaneously in both fast and slow growing types? We develop a population dynamical model of lineage expansion across a patchy environment, and find that mixed investment is favored across a broad range of environmental conditions, even when transmission is entirely via biofilm cells. This mixed strategy is favored because of a division of labor, where exponentially dividing planktonic cells can act as an engine for the production of future biofilm cells, which grow more slowly. We use experimental evolution to test our predictions, and show that phenotypic heterogeneity is persistent even under selection for purely planktonic or purely biofilm transmission. Furthermore, simulations suggest that maintenance of a biofilm subpopulation serves as a cost-effective hedge against environmental uncertainty, which is also consistent with our experimental findings.

microbiology↗

bioRxiv2016

Individual- versus group-optimality in the production of secreted bacterial compounds

How unicellular organisms optimize the production of compounds is a fundamental biological question. While it is typically thought that production is optimized at the individual-cell level, secreted compounds could also allow for optimization at the group level, leading to a division of labor where a subset of cells produces and shares the compound with everyone. Using mathematical modelling, we show that the evolution of such division of labor depends on the cost function of compound production. Specifically, for any trait with saturating benefits, linear costs promote the evolution of uniform production levels across cells. Conversely, production costs that diminish with higher output levels favor the evolution of specialization - especially when compound shareability is high. When experimentally testing these predictions with pyoverdine, a secreted iron-scavenging compound produced by Pseudomonas aeruginosa, we found linear costs and, consistent with our model, detected uniform pyoverdine production levels across cells. We conclude that for shared compounds with saturating benefits, the evolution of division of labor is facilitated by a diminishing cost function. More generally, we note that shifts in the level of selection from individuals to groups do not solely require cooperation, but critically depend on mechanistic factors, including the distribution of compound synthesis costs.

evolutionary biology↗