Shifting fire regimes cause continent-wide transformation of threatened species habitat.

Human actions are causing widespread increases in fire size, frequency, and severity in diverse ecosystems globally. This alteration of fire regimes is considered a threat to numerous animal species, but empirical evidence of how fire regimes are shifting within both threatened species' ranges and protected areas is scarce, particularly at large spatial and temporal scales. We used a big data approach to quantify multidecadal changes in fire regimes in southern Australia from 1980 to 2021, spanning 415 reserves (21.5 million ha) and 129 threatened species' ranges including birds, mammals, reptiles, invertebrates, and frogs. Most reserves and threatened species' ranges within the region have experienced declines in unburnt vegetation (≥30 y without fire), increases in recently burnt vegetation (≤5 y since fire), and increases in fire frequency. The mean percentage of unburnt vegetation within reserves declined from 61 to 36% (1980 to 2021), whereas the mean percentage of recently burnt vegetation increased from 20 to 35%, and mean fire frequency increased by 32%, with the latter two trends primarily driven by the record-breaking 2019 to 2020 fire season. The strongest changes occurred for high-elevation threatened species, and reserves of high elevation, high productivity, and strong rainfall decline, particularly in the southeast of the continent. Our results provide evidence for the widely held but poorly tested assumption that threatened species are experiencing widespread declines in unburnt habitat and increases in fire frequency. This underscores the imperative for developing management strategies that conserve fire-threatened species in an increasingly fiery future.

Tropical cyclone winds and precipitation stimulate cone production in the masting species longleaf pine (Pinus palustris).

Many trees exhibit masting - where reproduction is temporally variable and synchronous over large areas. Several dominant masting species occur in tropical cyclone (TC)-prone regions, but it is unknown whether TCs correlate with mast seeding. We analyzed long-term data (1958-2022) to test the hypothesis that TCs influence cone production in longleaf pine (Pinus palustris). We integrate field observations, weather data, satellite imagery, and hurricane models to test whether TCs influence cone production via: increased precipitation; canopy density reduction; and/or mechanical stress from wind. Cone production was 31% higher 1 yr after hurricanes and 71% higher after 2 yr, before returning to baseline levels. Cyclone-associated precipitation was correlated with increased cone production in wet years and cone production increased after low-intensity winds (≤ 25 m s-1 ) but not with high-intensity winds (> 25 m s-1 ). Tropical cyclones may stimulate cone production via precipitation addition, but high-intensity winds may offset any gains. Our study is the first to support the direct influence of TCs on reproduction, suggesting a previously unknown environmental correlate of masting, which may occur in hurricane-prone forests world-wide.

Extinction risk of the world's freshwater mammals.

The continued loss of freshwater habitats poses a significant threat to global biodiversity. We reviewed the extinction risk of 166 freshwater aquatic and semiaquatic mammals-a group rarely documented as a collective. We used the International Union for the Conservation of Nature Red List of Threatened Species categories as of December 2021 to determine extinction risk. Extinction risk was then compared among taxonomic groups, geographic areas, and biological traits. Thirty percent of all freshwater mammals were listed as threatened. Decreasing population trends were common (44.0%), including a greater rate of decline (3.6% in 20 years) than for mammals or freshwater species as a whole. Aquatic freshwater mammals were at a greater risk of extinction than semiaquatic freshwater mammals (95% CI -7.20 to -1.11). Twenty-nine species were data deficient or not evaluated. Large species (95% CI 0.01 to 0.03) with large dispersal distances (95% CI 0.03 to 0.15) had a higher risk of extinction than small species with small dispersal distances. The number of threatening processes associated with a species compounded their risk of extinction (95% CI 0.28 to 0.77). Hunting, land clearing for logging and agriculture, pollution, residential development, and habitat modification or destruction from dams and water management posed the greatest threats to these species. The basic life-history traits of many species were poorly known, highlighting the need for more research. Conservation of freshwater mammals requires a host of management actions centered around increased protection of riparian areas and more conscientious water management to aid the recovery of threatened species.

Riesgo de extinción de los mamíferos de agua dulce Resumen La pérdida continua de hábitats de agua dulce representa una amenaza importante para la biodiversidad mundial. Analizamos el riesgo de extinción de 166 especies de mamíferos acuáticos y semiacuáticos de agua dulce-un grupo que se documenta pocas veces como colectivo. Usamos las categorías de la Lista Roja de Especies Amenazadas de la Unión Internacional para la Conservación de la Naturaleza de diciembre 2021 para determinar el riesgo de extinción. Después comparamos este riesgo entre grupos taxonómicos, áreas geográficas y caracteres biológicos. El 30% de los mamíferos de agua dulce están categorizados como amenazados. La declinación de las tendencias poblacionales fue común (44.0%), incluyendo una mayor tasa de declinación (3.6% en 20 años) que para los mamíferos o las especies de agua dulce como conjunto. Los mamíferos acuáticos de agua dulce se encuentran en mayor riesgo de extinción que los mamíferos semiacuáticos (95% IC -7.20 a -1.11). Veintinueve especies no contaban con suficientes datos o no estaban evaluadas. Las especies grandes (95% IC 0.01 a 0.03) con distancias de dispersión amplias (95% IC 0.03 a 0.15) tuvieron un mayor riesgo de extinción que las especies pequeñas con menores distancias de dispersión. El número de procesos amenazantes asociados a alguna especie agravó su riesgo de extinción (95% CI 0.28 a 0.77). Las principales amenazas para estas especies fueron la cacería, el desmonte de tierras para tala y agricultura, la contaminación, los desarrollos residenciales y la destrucción o modificación del hábitat causados por presas o manejo hidrológico. Se sabe poco sobre los caracteres básicos de la historia de vida de muchas especies, lo que destaca la necesidad de más investigación al respecto. La conservación de mamíferos de agua dulce requiere una serie de acciones gestoras centradas en el incremento de la protección de las áreas ribereñas y una gestión hidrológica más consciente para ayudar a la recuperación de las especies amenazadas.

Bone Health ECHO Case Report: Fractures and Hypercalcemia in a Patient with Stage 5 Chronic Kidney Disease.

Bone Health ECHO (Extension for Community Healthcare Outcomes) is a virtual community of practice with the aim of enhancing global capacity to deliver best practice skeletal healthcare. The prototype program, established at the University of New Mexico, has been meeting online weekly since 2015, focusing on presentation and discussion of patient cases. These discussions commonly cover issues that are relevant to a broad range of patients, thereby serving as a force multiplier to improve the care of many patients. This is a case report from Bone Health ECHO about a patient with stage 5 chronic kidney disease, hypercalcemia, and low bone density, and the discussion that followed.

Herbaceous vegetation responses to experimental fire in savannas and forests depend on biome and climate.

Fire-vegetation feedbacks potentially maintain global savanna and forest distributions. Accordingly, vegetation in savanna and forest ecosystems should have differential responses to fire, but fire response data for herbaceous vegetation have yet to be synthesized across biomes. Here, we examined herbaceous vegetation responses to experimental fire at 30 sites spanning four continents. Across a variety of metrics, herbaceous vegetation increased in abundance where fire was applied, with larger responses to fire in wetter and in cooler and/or less seasonal systems. Compared to forests, savannas were associated with a 4.8 (±0.4) times larger difference in herbaceous vegetation abundance for burned versus unburned plots. In particular, grass cover decreased with fire exclusion in savannas, largely via decreases in C4 grass cover, whereas changes in fire frequency had a relatively weak effect on grass cover in forests. These differential responses underscore the importance of fire for maintaining the vegetation structure of savannas and forests.

Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

Targeted Protein Degradation Technology and Nanomedicine: Powerful Allies against Cancer.

Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential of targeting undruggable pathogenic proteins. After the first proof-of-concept proteolysis-targeting chimeric (PROTAC) molecule was reported, the TPD field has entered a new era. In addition to PROTAC, numerous novel TPD strategies have emerged to expand the degradation landscape. However, their physicochemical properties and uncontrolled off-target side effects have limited their therapeutic efficacy, raising concerns regarding TPD delivery system. The combination of TPD and nanotechnology offers great promise in improving safety and therapeutic efficacy. This review provides an overview of novel TPD technologies, discusses their clinical applications, and highlights the trends and perspectives in TPD nanomedicine.

Fire shapes fungal guild diversity and composition through direct and indirect pathways.

Fire has shaped global ecosystems for millennia by directly killing organisms and indirectly altering habitats and resources. All terrestrial ecosystems, including fire-prone ecosystems, rely on soil-inhabiting fungi, where they play vital roles in ecological processes. Yet our understanding of how fire regimes influence soil fungi remains limited and our knowledge of these interactions in semiarid landscapes is virtually absent. We collected soil samples and vegetation measurements from sites across a gradient in time-since-fire ages (0-75 years-since-fire) and fire frequency (burnt 0-5 times during the recent 29-year period) in a semiarid heathland of south-eastern Australia. We characterized fungal communities using ITS amplicon-sequencing and assigned fungi taxonomically to trophic guilds. We used structural equation models to examine direct, indirect and total effects of time-since-fire and fire frequency on total fungal, ectomycorrhizal, saprotrophic and pathogenic richness. We used multivariate analyses to investigate how total fungal, ectomycorrhizal, saprotrophic and pathogenic species composition differed between post-fire successional stages and fire frequency classes. Time-since-fire was an important driver of saprotrophic richness; directly, saprotrophic richness increased with time-since-fire, and indirectly, saprotrophic richness declined with time-since-fire (resulting in a positive total effect), mediated through the impact of fire on substrates. Frequently burnt sites had lower numbers of saprotrophic and pathogenic species. Post-fire successional stages and fire frequency classes were characterized by distinct fungal communities, with large differences in ectomycorrhizal species composition. Understanding the complex responses of fungal communities to fire can be improved by exploring how the effects of fire flow through ecosystems. Diverse fire histories may be important for maintaining the functional diversity of fungi in semiarid regions.

Identifying historical and future global change drivers that place species recovery at risk.

Ecosystem management in the face of global change requires understanding how co-occurring threats affect species and communities. Such an understanding allows for effective management strategies to be identified and implemented. An important component of this is differentiating between factors that are within (e.g. invasive predators) or outside (e.g. drought, large wildfires) of a local manager's control. In the global biodiversity hotspot of south-western Australia, small- and medium-sized mammal species are severely affected by anthropogenic threats and environmental disturbances, including invasive predators, fire, and declining rainfall. However, the relative importance of different drivers has not been quantified. We used data from a long-term monitoring program to fit Bayesian state-space models that estimated spatial and temporal changes in the relative abundance of four threatened mammal species: the woylie (Bettongia penicillata), chuditch (Dasyurus geoffroii), koomal (Trichosurus vulpecula) and quenda (Isoodon fusciventor). We then use Bayesian structural equation modelling to identify the direct and indirect drivers of population changes, and scenario analysis to forecast population responses to future environmental change. We found that habitat loss or conversion and reduced primary productivity (caused by rainfall declines) had greater effects on species' spatial and temporal population change than the range of fire and invasive predator (the red fox Vulpes vulpes) management actions observed in the study area. Scenario analysis revealed that a greater extent of severe fire and further rainfall declines predicted under climate change, operating in concert are likely to further reduce the abundance of these species, but may be mitigated partially by invasive predator control. Considering both historical and future drivers of population change is necessary to identify the factors that risk species recovery. Given that both anthropogenic pressures and environmental disturbances can undermine conservation efforts, managers must consider how the relative benefit of conservation actions will be shaped by ongoing global change.

Fire mosaics and habitat choice in nomadic foragers.

In the mid-1950s Western Desert of Australia, Aboriginal populations were in decline as families left for ration depots, cattle stations, and mission settlements. In the context of reduced population density, an ideal free-distribution model predicts landscape use should contract to the most productive habitats, and people should avoid areas that show more signs of extensive prior use. However, ecological or social facilitation due to Allee effects (positive density dependence) would predict that the intensity of past habitat use should correlate positively with habitat use. We analyzed fire footprints and fire mosaics from the accumulation of several years of landscape use visible on a 35,300-km2 mosaic of aerial photographs covering much of contemporary Indigenous Martu Native Title Lands imaged between May and August 1953. Structural equation modeling revealed that, consistent with an Allee ideal free distribution, there was a positive relationship between the extent of fire mosaics and the intensity of recent use, and this was consistent across habitats regardless of their quality. Fire mosaics build up in regions with low cost of access to water, high intrinsic food availability, and good access to trade opportunities; these mosaics (constrained by water access during the winter) then draw people back in subsequent years or seasons, largely independent of intrinsic habitat quality. Our results suggest that the positive feedback effects of landscape burning can substantially change the way people value landscapes, affecting mobility and settlement by increasing sedentism and local population density.

Distemper, extinction, and vaccination of the Amur tiger.

Canine distemper virus (CDV) has recently emerged as an extinction threat for the endangered Amur tiger (Panthera tigris altaica). CDV is vaccine-preventable, and control strategies could require vaccination of domestic dogs and/or wildlife populations. However, vaccination of endangered wildlife remains controversial, which has led to a focus on interventions in domestic dogs, often assumed to be the source of infection. Effective decision making requires an understanding of the true reservoir dynamics, which poses substantial challenges in remote areas with diverse host communities. We carried out serological, demographic, and phylogenetic studies of dog and wildlife populations in the Russian Far East to show that a number of wildlife species are more important than dogs, both in maintaining CDV and as sources of infection for tigers. Critically, therefore, because CDV circulates among multiple wildlife sources, dog vaccination alone would not be effective at protecting tigers. We show, however, that low-coverage vaccination of tigers themselves is feasible and would produce substantive reductions in extinction risks. Vaccination of endangered wildlife provides a valuable component of conservation strategies for endangered species.

A Community-Engaged Process for Adapting a Proven Community Health Worker Model to Integrate Precision Cancer Care Delivery for Low-income Latinx Adults With Cancer.

INTRODUCTION: Disparities in precision cancer care delivery among low-income Latinx adults are well described. In prior work, we developed a community health worker-led goals of care and cancer symptom assessment intervention. The objective of this study was to adapt this intervention for a community setting, incorporating precision cancer care delivery. METHODS: We used a two-phased systematic approach to adapt an evidence-based intervention for our community. Specifically, we used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to identify barriers and facilitators to precision cancer care delivery via 1-hr interviews with Latinx adults with cancer, Latinx caregivers, community leaders, primary care and oncology clinicians, and community health workers. Interviews were recorded, transcribed, and analyzed using the constant comparative method and grounded theory analysis. Phase 2 involved interviews with key community advisors using the Expert Panels Method to decide on final adaptations. RESULTS: Using this community-engaged approach, we identified specific intervention adaptations to ensure precision cancer care delivery in a community setting, which included: (a) expansion of the intervention inclusion criteria and mode of delivery; (b) integration of low-literacy precision cancer care intervention activities in Spanish in collaboration with community-based organizations; (c) ensuring goals reflective of patient and community priorities. CONCLUSIONS: This systematic and community-engaged approach to adapt an intervention for use in delivering precision cancer care strengthened an evidence-based approach to promote the needs and preferences of patients and key community stakeholders.

Animal mortality during fire.

Earth's rapidly warming climate is propelling us towards an increasingly fire-prone future. Currently, knowledge of the extent and characteristics of animal mortality rates during fire remains rudimentary, hindering our ability to predict how animal populations may be impacted in the future. To address this knowledge gap, we conducted a global systematic review of the direct effects of fire on animal mortality rates, based on studies that unequivocally determined the fate of animals during fire. From 31 studies spanning 1984-2020, we extracted data on the direct impacts of fire on the mortality of 31 species from 23 families. From these studies, there were 43 instances where direct effects were measured by reporting animal survival from pre- to post-fire. Most studies were conducted in North America (52%) and Oceania (42%), focused largely on mammals (53%) and reptiles (30%), and reported mostly on animal survival in planned (82%) and/or low severity (70%) fires. We found no studies from Asia, Europe or South America. Although there were insufficient data to conduct a formal meta-analysis, we tested the effect of fire type, fire severity, fire regime, animal body mass, ecological attributes and class on survival. Only fire severity affected animal mortality, with a higher proportion of animals being killed by high than low severity fires. Recent catastrophic fires across the globe have drawn attention to the plight of animals exposed to wildfire. Yet, our systematic review suggests that a relatively low proportion of animals (mean predicted mortality [95% CI] = 3% [1%-9%]) are killed during fire. However, our review also underscores how little we currently know about the direct effects of fire on animal mortality, and highlights the critical need to understand the effects of high severity fire on animal populations.

A comparison of different methods and materials for establishing maximal intercuspal position: A clinical study.

STATEMENT OF PROBLEM: Which method or material used to record the intercuspal position yields the best accuracy of location of the maxillary and mandibular casts is unclear. PURPOSE: The purpose of this clinical study was to determine the most reliable method of recording a patient's maximal intercuspal position by comparing 2 common methods with 2 popular registration materials. MATERIAL AND METHODS: Complete-arch impressions were made of both jaws with a polyvinyl siloxane impression material in a metal stock tray followed by 4 interocclusal registrations for each of the 17 participants. Two registration techniques were used. More than 1 record was obtained in the first technique, as the participant had to close through a wax sheet or a polyvinyl siloxane material. In the second technique, a polyvinyl siloxane material was injected from the buccal aspect between occluded tooth surfaces. Casts were made from Type 4 stone and vertical measurements of the casts were carried out by using digital vernier calipers, accurate to 100 µm. Hand articulation of the casts was used as the control. Consistency of measurement was assessed by the intraclass correlation coefficient, and comparisons were made by using repeated-measures regression analysis. RESULTS: Statistical analysis showed significant discrepancies when the participant closed through both wax and polyvinyl siloxane material (P<.001). No statistically significant differences to the control group were present when polyvinyl siloxane was injected laterally after closure. CONCLUSIONS: Hand articulation was the most accurate method of reproducing the maximal intercuspal position in a completely dentate individual with horizontal and vertical occlusal stability and was therefore considered the control. Recording the position after the participant had closed by using a polyvinyl siloxane material was the most accurate.

Cytotoxic and antitumor peptides as novel chemotherapeutics.

Covering: up to 2020Treatment resistance and drug-induced refractory malignancies pose significant challenges for current chemotherapy drugs. There have been increasing research efforts aimed at developing novel chemotherapeutics, especially from natural products and related derivatives. Natural cytotoxic peptides, an emerging source of chemotherapeutics, have exhibited the advantage of overcoming drug resistance and displayed broad-spectrum antitumor activities in the clinic. This highlight examines the increasingly popular cytotoxic peptides from isolated natural products. In-depth review of several peptides provides examples for how this novel strategy can lead to the improved anti-tumor effects. The mechanisms and current application of representative natural cytotoxic peptides (NCPs) have also been discussed, with a particular focus on future directions for interdisciplinary research.

Welcome to the Pyrocene: Animal survival in the age of megafire.

Planet Earth is entering the age of megafire, pushing ecosystems to their limits and beyond. While fire causes mortality of animals across vast portions of the globe, scientists are only beginning to consider fire as an evolutionary force in animal ecology. Here, we generate a series of hypotheses regarding animal responses to fire by adopting insights from the predator-prey literature. Fire is a lethal threat; thus, there is likely strong selection for animals to recognize the olfactory, auditory, and visual cues of fire, and deploy fire avoidance behaviours that maximize survival probability. If fire defences are costly, it follows that intraspecific variation in fire avoidance behaviours should correspond with variation in fire behaviour and regimes. Species and populations inhabiting ecosystems that rarely experience fire may lack these traits, placing 'fire naive' populations and species at enhanced extinction risk as the distribution of fire extends into new ecosystem types. We outline a research agenda to understand behavioural responses to fire and to identify conservation interventions that could be used to overcome fire naivety.

Fatty-acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses.

Endocannabinoids (eCBs) are lipid-signaling molecules involved in the regulation of numerous behaviors and physiological functions. Released by postsynaptic neurons, eCBs mediate retrograde modulation of synaptic transmission and plasticity by activating presynaptic cannabinoid receptors. While the cellular mechanisms by which eCBs control synaptic function have been well characterized, the mechanisms controlling their retrograde synaptic transport remain unknown. Here, we demonstrate that fatty-acid-binding protein 5 (FABP5), a canonical intracellular carrier of eCBs, is indispensable for retrograde eCB transport in the dorsal raphe nucleus (DRn). Thus, pharmacological inhibition or genetic deletion of FABP5 abolishes both phasic and tonic eCB-mediated control of excitatory synaptic transmission in the DRn. The blockade of retrograde eCB signaling induced by FABP5 inhibition is not mediated by impaired cannabinoid receptor function or reduced eCB synthesis. These findings indicate that FABP5 is essential for retrograde eCB signaling and may serve as a synaptic carrier of eCBs at central synapses.

Predator responses to fire: A global systematic review and meta-analysis.

Knowledge of how disturbances such as fire shape habitat structure and composition, and affect animal interactions, is fundamental to ecology and ecosystem management. Predators also exert strong effects on ecological communities, through top-down regulation of prey and competitors, which can result in trophic cascades. Despite their ubiquity, ecological importance and potential to interact with fire, our general understanding of how predators respond to fire remains poor, hampering ecosystem management. To address this important knowledge gap, we conducted a systematic review and meta-analysis of the effects of fire on terrestrial, vertebrate predators world-wide. We found 160 studies spanning 1978-2018. There were 36 studies with sufficient information for meta-analysis, from which we extracted 96 effect sizes (Hedges' g) for 67 predator species relating to changes in abundance indices, occupancy or resource selection in burned and unburned areas, or before and after fire. Studies spanned geographic locations, taxonomic families and study designs, but most were located in North America and Oceania (59% and 24%, respectively), and largely focussed on felids (24%) and canids (25%). Half (50%) of the studies reported responses to wildfire, and nearly one third concerned prescribed (management) fires. There were no clear, general responses of predators to fire, nor relationships with geographic area, biome or life-history traits (e.g. body mass, hunting strategy and diet). Responses varied considerably between species. Analysis of species for which at least three effect sizes had been reported in the literature revealed that red foxes Vulpes vulpes mostly responded positively to fire (e.g. higher abundance in burned compared to unburned areas) and eastern racers Coluber constrictor negatively, with variances overlapping zero only slightly for both species. Our systematic review and meta-analysis revealed strong variation in predator responses to fire, and major geographic and taxonomic knowledge gaps. Varied responses of predator species to fire likely depend on ecosystem context. Consistent reporting of ongoing monitoring and management experiments is required to improve understanding of the mechanisms driving predator responses to fire, and any broader effects (e.g. trophic interactions). The divergent responses of species in our study suggest that adaptive, context-specific management of predator-fire relationships is required.

Identification of Fatty Acid Binding Protein 5 Inhibitors Through Similarity-Based Screening.

Fatty acid binding protein 5 (FABP5) is a promising target for development of inhibitors to help control pain and inflammation. In this work, computer-based docking (DOCK6 program) was employed to screen ∼2 M commercially available compounds to FABP5 based on an X-ray structure complexed with the small molecule inhibitor SBFI-26 previously identified by our group (also through virtual screening). The goal was discovery of additional chemotypes. The screen resulted in the purchase of 78 candidates, which led to the identification of a new inhibitor scaffold (STK-0) with micromolar affinity and apparent selectivity for FABP5 over FABP3. A second similarity-based screen resulted in three additional hits (STK-15, STK-21, STK-22) from which preliminary SAR could be derived. Notably, STK-15 showed comparable activity to the SBFI-26 reference under the same assay conditions (1.40 vs 0.86 µM). Additional molecular dynamics simulations, free energy calculations, and structural analysis (starting from DOCK-generated poses) revealed that R enantiomers (dihydropyrrole scaffold) of STK-15 and STK-22 have a more optimal composition of functional groups to facilitate additional H-bonds with Arg109 of FABP5. This observation suggests enantiomerically pure compounds could show enhanced activity. Overall, our study highlights the utility of using similarity-based screening methods to discover new inhibitor chemotypes, and the identified FABP5 hits provide a strong starting point for future efforts geared to improve activity.

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 µg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.