scholarly journals Competition among Nasal Bacteria Suggests a Role for Siderophore-Mediated Interactions in Shaping the Human Nasal Microbiota

2018 ◽  
Vol 85 (10) ◽  
Author(s):  
Reed M. Stubbendieck ◽  
Daniel S. May ◽  
Marc G. Chevrette ◽  
Mia I. Temkin ◽  
Evelyn Wendt-Pienkowski ◽  
...  
Keyword(s):  
Nasal Cavity ◽  
Iron Acquisition ◽  
Interference Competition ◽  
Human Microbiome ◽  
Human Microbiome Project ◽  
Siderophore Production ◽  
Coagulase Negative Staphylococci ◽  
Exploitation Competition ◽  
Content Type

ABSTRACTResources available in the human nasal cavity are limited. Therefore, to successfully colonize the nasal cavity, bacteria must compete for scarce nutrients. Competition may occur directly through interference (e.g., antibiotics) or indirectly by nutrient sequestration. To investigate the nature of nasal bacterial competition, we performed coculture inhibition assays between nasalActinobacteriaandStaphylococcusspp. We found that isolates of coagulase-negative staphylococci (CoNS) were sensitive to growth inhibition byActinobacteriabut thatStaphylococcus aureusisolates were resistant to inhibition. AmongActinobacteria, we observed thatCorynebacteriumspp. were variable in their ability to inhibit CoNS. We sequenced the genomes of 10Corynebacteriumspecies isolates, including 3Corynebacterium propinquumisolates that strongly inhibited CoNS and 7 otherCorynebacteriumspecies isolates that only weakly inhibited CoNS. Using a comparative genomics approach, we found that theC. propinquumgenomes were enriched in genes for iron acquisition and harbored a biosynthetic gene cluster (BGC) for siderophore production, absent in the noninhibitoryCorynebacteriumspecies genomes. Using a chrome azurol S assay, we confirmed thatC. propinquumproduced siderophores. We demonstrated that iron supplementation rescued CoNS from inhibition byC. propinquum, suggesting that inhibition was due to iron restriction through siderophore production. Through comparative metabolomics and molecular networking, we identified the siderophore produced byC. propinquumas dehydroxynocardamine. Finally, we confirmed that the dehydroxynocardamine BGC is expressedin vivoby analyzing human nasal metatranscriptomes from the NIH Human Microbiome Project. Together, our results suggest that bacteria produce siderophores to compete for limited available iron in the nasal cavity and improve their fitness.IMPORTANCEWithin the nasal cavity, interference competition through antimicrobial production is prevalent. For instance, nasalStaphylococcusspecies strains can inhibit the growth of other bacteria through the production of nonribosomal peptides and ribosomally synthesized and posttranslationally modified peptides. In contrast, bacteria engaging in exploitation competition modify the external environment to prevent competitors from growing, usually by hindering access to or depleting essential nutrients. As the nasal cavity is a nutrient-limited environment, we hypothesized that exploitation competition occurs in this system. We determined thatCorynebacterium propinquumproduces an iron-chelating siderophore, and this iron-sequestering molecule correlates with the ability to inhibit the growth of coagulase-negative staphylococci. Furthermore, we found that the genes required for siderophore production are expressedin vivo. Thus, although siderophore production by bacteria is often considered a virulence trait, our work indicates that bacteria may produce siderophores to compete for limited iron in the human nasal cavity.

scholarly journals Bacterial competition mediated by siderophore production among the human nasal microbiota

2018 ◽  
Author(s):  
Reed M. Stubbendieck ◽  
Daniel S. May ◽  
Marc G. Chevrette ◽  
Mia I. Temkin ◽  
Evelyn Wendt-Pienkowski ◽  
...  
Keyword(s):  
Nasal Cavity ◽  
Staphylococcus Epidermidis ◽  
Iron Acquisition ◽  
Interference Competition ◽  
Human Microbiome ◽  
Human Microbiome Project ◽  
Siderophore Production ◽  
Exploitation Competition ◽  
Bacterial Competition

ABSTRACTResources available in the human nasal cavity are limited. Therefore, to successfully colonize the nasal cavity, bacteria must compete for scarce nutrients. Competition may occur directly through interference (e.g., antibiotics) or indirectly by nutrient sequestration. To investigate the nature of nasal bacterial competition, we performed co-culture inhibition assays between nasal Actinobacteria andStaphylococcusspp. We found thatStaphylococcus epidermidisisolates were sensitive to growth inhibition by Actinobacteria butStaphylococcus aureusisolates were resistant to inhibition. Among Actinobacteria, we observed thatCorynebacteriumspp. were variable in their ability to inhibitS. epidermidis.We sequenced the genomes of tenCorynebacteriumspp. isolates, including threeCorynebacterium propinquumthat strongly inhibitedS. epidermidisand seven otherCorynebacteriumspp. isolates that only weakly inhibitedS. epidermidis.Using a comparative genomics approach, we found that theC. propinquumgenomes were enriched in genes for iron acquisition and encoded a biosynthetic gene cluster (BGC) for siderophore production, absent in the non-inhibitoryCorynebacteriumspp. genomes. Using a chromeazurol S assay, we confirmed thatC. propinquumproduced siderophores. We demonstrated that iron supplementation rescuedS. epidermidisfrom inhibition byC. propinquum, suggesting that inhibition was due to iron restriction through siderophore production. Using comparative metabolomics, we identified the siderophore produced byC. propinquumas dehydroxynocardamine. Finally, we confirmed that the dehydroxynocardamine BGC is expressedin vivoby analyzing human nasal metatranscriptomes from the NIH Human Microbiome Project.Together, our results suggest that bacteria produce siderophores to compete for limited available iron in the nasal cavity and improve their fitness.IMPORTANCEWithin the nasal cavity, interference competition through antimicrobial production is prevalent. For instance, nasalStaphylococcusspp. strains can inhibit the growth of other bacteria through the production of nonribosomal peptides and ribosomally synthesized and post-translationally modified peptides. In contrast, bacteria engaging in exploitation competition modify the external environment to prevent competitors from growing, usually by depleting access to essential nutrients. As the nasal cavity is a nutrient limited environment, we hypothesized that exploitation competition occurs in this system. We determined thatCorynebacterium propinquumproduces an iron-chelating siderophore and is able to use this molecule to sequester iron and inhibit the growth ofStaphylococcus epidermidis.Further, we found that the genes required for siderophore production are expressedin vivo.Thus, though siderophore production by bacteria is often considered a virulence trait, our work indicates that bacteria may produce siderophores to compete for limited iron in the human nasal cavity.

scholarly journals Sequence Comparison of Vaginolysin from Different Gardnerella Species

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 86
Author(s):  
Erin M. Garcia ◽  
Myrna G. Serrano ◽  
Laahirie Edupuganti ◽  
David J. Edwards ◽  
Gregory A. Buck ◽  
...  
Keyword(s):  
Amino Acid ◽  
Human Microbiome ◽  
Human Microbiome Project ◽  
Distinct Species ◽  
Vaginal Swab ◽  
Metagenomic Data ◽  
Gardnerella Vaginalis ◽  
Vaginal Epithelial Cells ◽  
Species Specific

Gardnerella vaginalis has recently been split into 13 distinct species. In this study, we tested the hypotheses that species-specific variations in the vaginolysin (VLY) amino acid sequence could influence the interaction between the toxin and vaginal epithelial cells and that VLY variation may be one factor that distinguishes less virulent or commensal strains from more virulent strains. This was assessed by bioinformatic analyses of publicly available Gardnerella spp. sequences and quantification of cytotoxicity and cytokine production from purified, recombinantly produced versions of VLY. After identifying conserved differences that could distinguish distinct VLY types, we analyzed metagenomic data from a cohort of female subjects from the Vaginal Human Microbiome Project to investigate whether these different VLY types exhibited any significant associations with symptoms or Gardnerella spp.-relative abundance in vaginal swab samples. While Type 1 VLY was most prevalent among the subjects and may be associated with increased reports of symptoms, subjects with Type 2 VLY dominant profiles exhibited increased relative Gardnerella spp. abundance. Our findings suggest that amino acid differences alter the interaction of VLY with vaginal keratinocytes, which may potentiate differences in bacterial vaginosis (BV) immunopathology in vivo.

scholarly journals Dopamine Is a Siderophore-Like Iron Chelator That PromotesSalmonella entericaSerovar Typhimurium Virulence in Mice

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Stefanie Dichtl ◽  
Egon Demetz ◽  
David Haschka ◽  
Piotr Tymoszuk ◽  
Verena Petzer ◽  
...  
Keyword(s):  
Bacterial Growth ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Lipocalin 2 ◽  
Intracellular Iron ◽  
Content Type ◽  
Hepcidin Expression

ABSTRACTWe have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course ofSalmonellainfections. Dopamine was found to promote the growth ofSalmonellaboth in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected withSalmonella entericaserovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth.Salmonellalacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria.IMPORTANCEHere we show that dopamine increases bacterial iron incorporation and promotesSalmonellaTyphimurium growth bothin vitroandin vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

scholarly journals Multifunctional Nutrient-Binding Proteins Adapt Human Symbiotic Bacteria for Glycan Competition in the Gut by Separately Promoting Enhanced Sensing and Catalysis

mBio ◽  
2014 ◽  
Vol 5 (5) ◽  
Author(s):  
Elizabeth A. Cameron ◽  
Kurt J. Kwiatkowski ◽  
Byung-Hoo Lee ◽  
Bruce R. Hamaker ◽  
Nicole M. Koropatkin ◽  
...  
Keyword(s):  
Binding Sites ◽  
Binding Proteins ◽  
Human Microbiome ◽  
Gut Bacteria ◽  
Nutrient Acquisition ◽  
Carbohydrate Binding ◽  
Content Type ◽  
Carbohydrate Binding Proteins ◽  
Gnotobiotic Mice

ABSTRACT To compete for the dynamic stream of nutrients flowing into their ecosystem, colonic bacteria must respond rapidly to new resources and then catabolize them efficiently once they are detected. The Bacteroides thetaiotaomicron starch utilization system (Sus) is a model for nutrient acquisition by symbiotic gut bacteria, which harbor thousands of related Sus-like systems. Structural investigation of the four Sus outer membrane proteins (SusD, -E, -F, and -G) revealed that they contain a total of eight starch-binding sites that we demonstrated, using genetic and biochemical approaches, to play distinct roles in starch metabolism in vitro and in vivo in gnotobiotic mice. SusD, whose homologs are abundant in the human microbiome, is critical for the initial sensing of available starch, allowing sus transcriptional activation at much lower concentrations than without this function. In contrast, seven additional binding sites across SusE, -F, and -G are dispensable for sus activation. However, they optimize the rate of growth on starch in a manner dependent on the expression of the bacterial polysaccharide capsule, suggesting that they have evolved to offset the diffusion barrier created by this structure. These findings demonstrate how proteins with similar biochemical behavior can serve orthogonal functions during different stages of cellular adaptation to nutrients. Finally, we demonstrated in gnotobiotic mice fed a starch-rich diet that the Sus binding sites confer a competitive advantage to B. thetaiotaomicron in vivo in a manner that is dependent on other colonizing microbes. This study reveals how numerically dominant families of carbohydrate-binding proteins in the human microbiome fulfill separate and sometimes cooperative roles to optimize gut commensal bacteria for nutrient acquisition. IMPORTANCE Our intestinal tract harbors trillions of symbiotic microbes. A critical function contributed by this microbial community is the ability to degrade most of the complex carbohydrates in our diet, which not only change from meal to meal but also cannot be digested by our own bodies. A numerically abundant group of gut bacteria called the Bacteroidetes plays a prominent role in carbohydrate digestion in humans and other animals. Currently, the mechanisms that allow this bacterial group to rapidly respond to available carbohydrates and then digest them efficiently are unclear. Here, we present novel functions for four carbohydrate-binding proteins present in one member of the Bacteroidetes, revealing that these proteins serve unique and separable roles in either initial nutrient sensing or subsequent digestion. Because the protein families investigated are numerous in other gut bacteria colonizing nearly all humans and animals, our findings are fundamentally important to understanding how symbiotic microbes assist human digestion.

scholarly journals Pharmacokinetic andIn VivoEfficacy Studies of the Mycobactin Biosynthesis Inhibitor Salicyl-AMS in Mice

2013 ◽  
Vol 57 (10) ◽  
pp. 5138-5140 ◽  
Author(s):  
Shichun Lun ◽  
Haidan Guo ◽  
John Adamson ◽  
Justin S. Cisar ◽  
Tony D. Davis ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Single Dose ◽  
Iron Acquisition ◽  
Mouse Lung ◽  
Proof Of Concept ◽  
Content Type ◽  
Biosynthesis Inhibitor ◽  
Parameter Values

ABSTRACTMycobactin biosynthesis inMycobacterium tuberculosisfacilitates iron acquisition, which is required for growth and virulence. The mycobactin biosynthesis inhibitor salicyl-AMS [5′-O-(N-salicylsulfamoyl)adenosine] inhibitsM. tuberculosisgrowthin vitrounder iron-limited conditions. Here, we conducted a single-dose pharmacokinetic study and a monotherapy study of salicyl-AMS with mice. Intraperitoneal injection yielded much better pharmacokinetic parameter values than oral administration did. Monotherapy of salicyl-AMS at 5.6 or 16.7 mg/kg significantly inhibitedM. tuberculosisgrowth in the mouse lung, providing the firstin vivoproof of concept for this novel antibacterial strategy.

scholarly journals Role of Acinetobactin-Mediated Iron Acquisition Functions in the Interaction of Acinetobacter baumannii Strain ATCC 19606Twith Human Lung Epithelial Cells, Galleria mellonella Caterpillars, and Mice

2012 ◽  
Vol 80 (3) ◽  
pp. 1015-1024 ◽  
Author(s):  
Jennifer A. Gaddy ◽  
Brock A. Arivett ◽  
Michael J. McConnell ◽  
Rafael López-Rojas ◽  
Jerónimo Pachón ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Ex Vivo ◽  
Iron Acquisition ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Content Type ◽  
Alveolar Epithelial

Acinetobacter baumannii, which causes serious infections in immunocompromised patients, expresses high-affinity iron acquisition functions needed for growth under iron-limiting laboratory conditions. In this study, we determined that the initial interaction of the ATCC 19606Ttype strain with A549 human alveolar epithelial cells is independent of the production of BasD and BauA, proteins needed for acinetobactin biosynthesis and transport, respectively. In contrast, these proteins are required for this strain to persist within epithelial cells and cause their apoptotic death. Infection assays usingGalleria mellonellalarvae showed that impairment of acinetobactin biosynthesis and transport functions significantly reduces the ability of ATCC 19606Tcells to persist and kill this host, a defect that was corrected by adding inorganic iron to the inocula. The results obtained with theseex vivoandin vivoapproaches were validated using a mouse sepsis model, which showed that expression of the acinetobactin-mediated iron acquisition system is critical for ATCC 19606Tto establish an infection and kill this vertebrate host. These observations demonstrate that the virulence of the ATCC 19606Tstrain depends on the expression of a fully active acinetobactin-mediated system. Interestingly, the three models also showed that impairment of BasD production results in an intermediate virulence phenotype compared to those of the parental strain and the BauA mutant. This observation suggests that acinetobactin intermediates or precursors play a virulence role, although their contribution to iron acquisition is less relevant than that of mature acinetobactin.

scholarly journals Siderophore-Mediated Iron Acquisition Plays a Critical Role in Biofilm Formation and Survival of Staphylococcus epidermidis Within the Host

2021 ◽  
Vol 8 ◽  
Author(s):  
Fernando Oliveira ◽  
Tânia Lima ◽  
Alexandra Correia ◽  
Ana Margarida Silva ◽  
Cristina Soares ◽  
...  
Keyword(s):  
Staphylococcus Epidermidis ◽  
Iron Acquisition ◽  
Critical Role ◽  
Siderophore Production ◽  
Restricted Environment ◽  
Underlying Mechanisms ◽  
First Time ◽  
Comprehensive Study

Iron acquisition through siderophores, a class of small, potent iron-chelating organic molecules, is a widely spread strategy among pathogens to survive in the iron-restricted environment found in the host. Although these molecules have been implicated in the pathogenesis of several species, there is currently no comprehensive study addressing siderophore production in Staphylococcus epidermidis. Staphylococcus epidermidis is an innocuous skin commensal bacterium. The species, though, has emerged as a leading cause of implant-associated infections, significantly supported by an inherent ability to form biofilms. The process of adaptation from skin niche environments to the hostile conditions during invasion is yet not fully understood. Herein, we addressed the possible role of siderophore production in S. epidermidis virulence. We first identified and deleted a siderophore homolog locus, sfaABCD, and provided evidence for its involvement in iron acquisition. Our findings further suggested the involvement of siderophores in the protection against oxidative stress-induced damage and demonstrated the in vivo relevance of a siderophore-mediated iron acquisition during S. epidermidis infections. Conclusively, this study addressed, for the first time in this species, the underlying mechanisms of siderophore production, highlighting the importance of a siderophore-mediated iron acquisition under host relevant conditions and, most importantly, its contribution to survival within the host.

scholarly journals Analysis of theIn VivoTranscriptome ofBordetella pertussisduring Infection of Mice

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Ting Y. Wong ◽  
Jesse M. Hall ◽  
Evan S. Nowak ◽  
Dylan T. Boehm ◽  
Laura A. Gonyar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Iron Acquisition ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Growth Conditions ◽  
Rna Seq ◽  
Content Type ◽  
Murine Lung

ABSTRACTBordetella pertussiscauses the disease whooping cough through coordinated control of virulence factors by theBordetellavirulence gene system. Microarrays and, more recently, RNA sequencing (RNA-seq) have been used to describein vitrogene expression profiles ofB. pertussisand other pathogens. In previous studies, we have analyzed thein vitrogene expression profiles ofB. pertussis, and we hypothesize that the infection transcriptome profilein vivois significantly different from that under laboratory growth conditions. To study the infection transcriptome ofB. pertussis, we developed a simple filtration technique for isolation of bacteria from infected lungs. The work flow involves filtering the bacteria out of the lung homogenate using a 5-μm-pore-size syringe filter. The captured bacteria are then lysed to isolate RNA for Illumina library preparation and RNA-seq analysis. Upon comparing thein vitroandin vivogene expression profiles, we identified 351 and 255 genes as activated and repressed, respectively, during murine lung infection. As expected, numerous genes associated with virulent-phase growth were activated in the murine host, including pertussis toxin (PT), the PT secretion apparatus, and the type III secretion system. A significant number of genes encoding iron acquisition and heme uptake proteins were highly expressed during infection, supporting iron acquisition as critical forB. pertussissurvivalin vivo. Numerous metabolic genes were repressed during infection. Overall, these data shed light on the gene expression profile ofB. pertussisduring infection, and this method will facilitate efforts to understand how this pathogen causes infection.IMPORTANCEIn vitrogrowth conditions for bacteria do not fully recapitulate the host environment. RNA sequencing transcriptome analysis allows for the characterization of the infection gene expression profiles of pathogens in complex environments. Isolation of the pathogen from infected tissues is critical because of the large amounts of host RNA present in crude lysates of infected organs. A filtration method was developed that enabled enrichment of the pathogen RNA for RNA-seq analysis. The resulting data describe the “infection transcriptome” ofB. pertussisin the murine lung. This strategy can be utilized for pathogens in other hosts and, thus, expand our knowledge of what bacteria express during infection.

scholarly journals Adaptation-Based Resistance to Siderophore-Conjugated Antibacterial Agents by Pseudomonas aeruginosa

2013 ◽  
Vol 57 (9) ◽  
pp. 4197-4207 ◽  
Author(s):  
Andrew P. Tomaras ◽  
Jared L. Crandon ◽  
Craig J. McPherson ◽  
Mary Anne Banevicius ◽  
Steven M. Finegan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibacterial Agents ◽  
Iron Acquisition ◽  
Content Type ◽  
Multiple Strains ◽  
Resistance Rates ◽  
Assay Conditions

ABSTRACTMultidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed to combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, has received significant attention in recent years. While standardin vitroMIC and resistance frequency methods demonstrate that these compounds are potent, broad-spectrum antibacterial agents whose activity should not be threatened by unacceptably high spontaneous resistance rates, recapitulation of these results in animal models can prove unreliable, partially because of the differences in iron availability in these different methods. Here, we describe the characterization of MB-1, a novel siderophore-conjugated monobactam that demonstrates excellentin vitroactivity againstPseudomonas aeruginosawhen tested using standard assay conditions. Unfortunately, thein vitrofindings did not correlate with thein vivoresults we obtained, as multiple strains were not effectively treated by MB-1 despite having low MICs. To address this, we also describe the development of newin vitroassays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of someP. aeruginosaisolatesin vivo.

scholarly journals Mode of Action,In VitroActivity, andIn VivoEfficacy of AFN-1252, a Selective Antistaphylococcal FabI Inhibitor

2012 ◽  
Vol 56 (11) ◽  
pp. 5865-5874 ◽  
Author(s):  
Nachum Kaplan ◽  
Monique Albert ◽  
Donald Awrey ◽  
Elias Bardouniotis ◽  
Judd Berman ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Fatty Acid Biosynthesis ◽  
Acyl Carrier Protein ◽  
Pharmacokinetic Studies ◽  
Coagulase Negative Staphylococci ◽  
Resistance Development ◽  
Content Type ◽  
Peritoneal Infection

ABSTRACTThe mechanism of action of AFN-1252, a selective inhibitor ofStaphylococcus aureusenoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis, was confirmed by using biochemistry, macromolecular synthesis, genetics, and cocrystallization of an AFN-1252–FabI complex. AFN-1252 demonstrated a low propensity for spontaneous resistance development and a time-dependent reduction of the viability of both methicillin-susceptible and methicillin-resistantS. aureus, achieving a ≥2-log10reduction inS. aureuscounts over 24 h, and was extremely potent against clinical isolates ofS. aureus(MIC90, 0.015 μg/ml) and coagulase-negative staphylococci (MIC90, 0.12 μg/ml), regardless of their drug resistance, hospital- or community-associated origin, or other clinical subgroup. AFN-1252 was orally available in mouse pharmacokinetic studies, and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia, providing 100% protection from an otherwise lethal peritoneal infection ofS. aureusSmith. A median effective dose of 0.15 mg/kg indicated that AFN-1252 was 12 to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potentin vitroactivity, andin vivoefficacy, support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.

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