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A rare and possibly fatal infection of the bone called emphysematous osteomyelitis (EO) is caused by the presence of intraosseous gas due to gas-forming organisms. Common gas-producing organisms are in the Enterobacteriaceae family or are anaerobes. This gas within bones is most frequently detected using computed tomography (CT) imaging, and prompt diagnosis is important due to the high mortality rate. We present a 76-year-old male who complained of altered mental status, right upper and lower extremity weakness, and lower back pain. The MRI of the lumbar spine showed moderate edema in L3 and L4, with fluid in L3-L4 and L4-L5 concerning discitis/osteomyelitis. A CT-guided biopsy of L3/L4 was then performed by interventional radiology, revealing air present in the L3 and L4 vertebral bodies. Bone cultures from the L3 and L4 vertebra were later positive for E. coli that was susceptible to all tested antibiotics, and this was consistent with a diagnosis of vertebral EO. The infectious disease team recommended a six-week course of intravenous ceftriaxone. During the patient's hospital stay, he also developed a septic right knee joint positive for E. coli, alongwith the concurrent vertebral EO.
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Gardnerella vaginalis is a rare cause of symptomatic urethritis and prostatitis in sexually active men. There are limited cases in the literature and few treatment recommendations. Treatment with metronidazole or clindamycin of both sexual partners may provide resolution of symptoms in these men.
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Histoplasma capsulatum can rarely affect the trachea. We report the case of a 68-year-old woman with rheumatoid arthritis on immunosuppressive therapy who presented with fevers, worsening shortness of breath, nonproductive cough and subjective throat hoarseness and fullness. Chest computed tomography demonstrated no tracheal findings. Bronchoscopy found mucosal irregularity, nodularity and vesicular regions in the proximal trachea extending seven centimeters distal to the vocal cords. Also seen was an edematous, exudative left vocal cord with polyps and an ulcerative lesion. Silver staining and culture and wash of the tracheal biopsy revealed Histoplasma capsulatum. She was treated with oral itraconazole then briefly on intravenous amphotericin for rising Histoplasma urinary antigen levels. She continued treatment 24 months following diagnosis with minimal dyspnea. Histoplasma tracheitis has been proposed as an indicator of disseminated infection. However, our patient did not demonstrate other organ manifestations. Histoplasma tracheitis should be considered in a differential diagnosis of tracheal lesions even in the absence of systemic involvement.
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Anfotericina B/administración & dosificación , Histoplasmosis/diagnóstico , Itraconazol/administración & dosificación , Tráquea/microbiología , Administración Intravenosa , Anciano , Anfotericina B/uso terapéutico , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Diagnóstico Diferencial , Femenino , Histoplasma/aislamiento & purificación , Histoplasmosis/tratamiento farmacológico , Humanos , Itraconazol/uso terapéutico , Tráquea/patología , Resultado del TratamientoRESUMEN
Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.
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Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Tiohidantoínas/uso terapéutico , Antagonistas de Andrógenos/farmacocinética , Anilidas/farmacocinética , Anilidas/uso terapéutico , Animales , Antineoplásicos Hormonales/sangre , Antineoplásicos Hormonales/farmacocinética , Benzamidas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Nitrilos/farmacocinética , Nitrilos/uso terapéutico , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/sangre , Feniltiohidantoína/farmacocinética , Feniltiohidantoína/uso terapéutico , Ratas , Receptores Androgénicos/efectos de los fármacos , Tiohidantoínas/sangre , Tiohidantoínas/síntesis química , Tiohidantoínas/farmacocinética , Compuestos de Tosilo/farmacocinética , Compuestos de Tosilo/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We have identified and synthesized a series of imidazole containing dimerization inhibitors of inducible nitric oxide synthase (iNOS). The necessity of key imidazole and piperonyl functionality was demonstrated and SAR studies led to the identification of compound 35, which showed a dose dependant inhibition in multiple pain models, including tactile allodynia induced by spinal nerve ligation (Chung model).
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Imidazoles/química , Imidazoles/uso terapéutico , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Multimerización de Proteína/efectos de los fármacos , Animales , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Imidazoles/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Endogámicas LewRESUMEN
Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes.
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Hidroxiquinolinas/síntesis química , Quinolinas/química , Receptores Acoplados a Proteínas G/agonistas , Tiofenos/síntesis química , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/metabolismo , Hidroxiquinolinas/química , Hidroxiquinolinas/uso terapéutico , Ratones , Quinolinas/síntesis química , Quinolinas/uso terapéutico , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/uso terapéuticoRESUMEN
The transcription of inducible nitric oxide synthase (iNOS) is activated by a network of proinflammatory signaling pathways. Here we describe the identification of a small molecule that downregulates the expression of iNOS mRNA and protein in cytokine-activated cells and suppresses nitric oxide production in vivo. Mechanistic analysis suggests that this small molecule, erstressin, also activates the unfolded protein response (UPR), a signaling pathway triggered by endoplasmic reticulum stress. Erstressin induces rapid phosphorylation of eIF2alpha and the alternative splicing of XBP-1, hallmark initiating events of the UPR. Further, erstressin activates the transcription of multiple genes involved in the UPR. These data suggest an inverse relationship between UPR activation and iNOS mRNA and protein expression under proinflammatory conditions.
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ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.
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Diseño de Fármacos , Guanosina/análogos & derivados , Profármacos/administración & dosificación , Profármacos/síntesis química , Pirimidinonas/administración & dosificación , Pirimidinonas/síntesis química , Receptor Toll-Like 7/agonistas , Administración Oral , Antivirales/farmacología , Guanosina/farmacología , Humanos , Profármacos/química , Profármacos/farmacocinética , Pirimidinonas/química , Pirimidinonas/farmacocinéticaRESUMEN
BACKGROUND: A potentially lethal flux of hydrogen peroxide (H2O2) is continuously generated during aerobic metabolism. It follows that aerobic organisms have equipped themselves with specific H2O2 dismutases and H2O2 reductases, of which catalase and the alkyl hydroperoxide reductase (AhpR) are the best-studied prokaryotic members. The sequenced Haemophilus influenzae Rd genome reveals one catalase, designated HktE, and no AhpR. However, Haemophilus influenzae type b strain Eagan (Hib), a causative agent of bacterial sepsis and meningitis in young children, disrupted in its hktE gene is not attenuated in virulence, and retains the ability to rapidly scavenge H2O2. This redundancy in H2O2-scavenging is accounted for by peroxidatic activity which specifically uses glutathione as the reducing substrate. RESULTS: We show here that inside acatalasaemic H. influenzae all of the residual peroxidatic activity is catalyzed by PGdx, a hybrid peroxiredoxin-glutaredoxin glutathione-dependent peroxidase. In vitro kinetic assays on crude hktE- pgdx- H. influenzae Rd extracts revealed the presence of NAD(P)H:peroxide oxidoreductase activity, which, however, appears to be physiologically insignificant because of its low affinity for H2O2 (Km = 1.1 mM). Hydroperoxidase-deficient hktE- pgdx- H. influenzae Rd showed a slightly affected aerobic growth phenotype in rich broth, while, in chemically defined medium, growth was completely inhibited by aerobic conditions, unless the medium contained an amino acid/vitamin supplement. To study the role of PGdx in virulence and to assess the requirement of H2O2-scavenging during the course of infection, both a pgdx single mutant and a pgdx/hktE double mutant of Hib were assayed for virulence in an infant rat model. The ability of both mutant strains to cause bacteremia was unaffected. CONCLUSION: Catalase (HktE) and a sole peroxidase (PGdx) account for the majority of scavenging of metabolically generated H2O2 in the H. influenzae cytoplasm. Growth experiments with hydroperoxidase-deficient hktE- pgdx- H. influenzae Rd suggest that the cytotoxicity inflicted by the continuous accumulation of H2O2 during aerobic growth brings about bacteriostasis rather than bacterial killing. Finally, H2O2-scavenging is not a determinant of Hib virulence in the infant rat model of infection.
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Depuradores de Radicales Libres/metabolismo , Haemophilus influenzae tipo b/metabolismo , Haemophilus influenzae tipo b/patogenicidad , Peróxido de Hidrógeno/metabolismo , Catalasa/genética , Catalasa/metabolismo , Eliminación de Gen , Haemophilus influenzae tipo b/enzimología , Haemophilus influenzae tipo b/genética , Mutación , Estrés Oxidativo , Peroxidasas/genética , Peroxidasas/metabolismo , VirulenciaRESUMEN
The transcription factors lymphoid enhancer binding factor 1 (LEF1) and transcription factor 7 (TCF7) (T cell factor-1 (TCF-1)) are downstream effectors of the WNT signaling pathway, which is a critical regulator of T cell development in the thymus. In this study, we show that LEF1 and TCF7 (TCF-1) are not only expressed in thymocytes, but also in mature T cells. Our data demonstrate that Ag encounter in vivo and engagement of the TCR or IL-15 receptor in vitro leads to the down-regulation of LEF1 and TCF7 (TCF-1) expression in human naive CD8 T cells. We further show that resting T cells preferentially express inhibitory LEF1 and TCF7 (TCF-1) isoforms and that T cell activation changes the isoform balance in favor of stimulatory TCF7 (TCF-1) isoforms. Altogether, our study suggests that proteins involved in the WNT signaling pathway not only regulate T cell development, but also peripheral T cell differentiation.
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Antígenos/fisiología , Linfocitos T CD8-positivos/inmunología , Regulación hacia Abajo/inmunología , Factor de Unión 1 al Potenciador Linfoide/antagonistas & inhibidores , Fase de Descanso del Ciclo Celular/inmunología , Transducción de Señal/inmunología , Factor 1 de Transcripción de Linfocitos T/antagonistas & inhibidores , Proteínas Wnt/antagonistas & inhibidores , Linfocitos T CD8-positivos/citología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Perfilación de la Expresión Génica , Humanos , Interleucina-15/fisiología , Factor de Unión 1 al Potenciador Linfoide/biosíntesis , Factor de Unión 1 al Potenciador Linfoide/genética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Receptores de Antígenos de Linfocitos T/fisiología , Fase de Descanso del Ciclo Celular/genética , Transducción de Señal/genética , Factor 1 de Transcripción de Linfocitos T/biosíntesis , Factor 1 de Transcripción de Linfocitos T/genética , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Proteínas Wnt/biosíntesisRESUMEN
Digalactoside (galalpha-1-4 galbeta) structures of the lipopolysaccharide (LPS) of Haemophilus influenzae are implicated in virulence. A confounding factor is that tetranucleotide repeats within the lic2A, lgtC, and lex2 genes mediate phase-variable expression of the digalactosides. By deleting these repeats, we constructed recombinant strains of RM153 constitutively expressing either one or two LPS digalactosides. Expression of two digalactosides, rather than one, was associated with increased virulence of H. influenzae in vivo.
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Bacteriemia/microbiología , Disacáridos/metabolismo , Infecciones por Haemophilus/microbiología , Haemophilus influenzae/genética , Haemophilus influenzae/patogenicidad , Lipopolisacáridos/biosíntesis , Animales , Proteínas Bacterianas/genética , Secuencia de Carbohidratos , Disacáridos/análisis , Genes Bacterianos/genética , Lipopolisacáridos/química , Datos de Secuencia Molecular , Ratas , Ratas Sprague-Dawley , Eliminación de SecuenciaRESUMEN
Diagnosing genetic disorders and counselling the parents of babies with possible genetic conditions takes up a significant proportion of a neonatologist's clinical time. This article provides a guide to establishing genetic tools and a reference library on a neonatal unit. The availability of good resources may heighten staff awareness of genetic aetiologies in babies with subtle features, and enable possible diagnoses to be considered and a genetics consultation sought. In addition, when a diagnosis is made, information is then readily available to guide the neonatologist in his or her consultations with parents. It is not intended that the tools outlined here should be a replacement for the genetics consultation; their role is merely to facilitate the interaction of neonatologists with geneticists, to the benefit of the parents and the baby.
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Genética , Neonatología , Bases de Datos Genéticas , Humanos , Internet , Obras de ReferenciaRESUMEN
BACKGROUND: Streptococcus agalactiae (Group B Streptococcus; GBS) is a major contributor to obstetric and neonatal bacterial sepsis. Serotype III strains cause the majority of late-onset sepsis and meningitis in babies, and thus appear to have an enhanced invasive capacity compared with the other serotypes that cause disease predominantly in immunocompromised pregnant women. We compared the serotype III and V whole genome sequences, strains NEM316 and 2603VR respectively, in an attempt to identify genetic attributes of strain NEM316 that might explain the propensity of strain NEM316 to cause late-onset disease in babies. Fourteen putative pathogenicity islands were described in the strain NEM316 whole genome sequence. Using PCR- and targeted microarray- strategies, the presence of these islands were assessed in a diverse strain collection including 18 colonizing isolates from healthy pregnant women, and 13 and 8 invasive isolates from infants with early- and late-onset sepsis, respectively. RESULTS: Side-by-side comparison of the strain NEM316 and strain 2603VR genomes revealed that they are extremely similar, with the only major difference being the capsulation loci and mobile genetic elements. PCR and Comparative Genome Hybridization (CGH) were used to define the presence of each island in 39 GBS isolates. Only islands I, VI, XII, and possibly X, met criteria of a true pathogenicity island, but no significant correlation was found between the presence of any of the fourteen islands and whether the strains were invasive or colonizing. Possible associations were seen between the presence of island VI and late-onset sepsis, and island X and early-onset sepsis, which warrant further investigation. CONCLUSION: The NEM316 and 2603VR strains are remarkable in that their whole genome sequences are so similar, suggesting that the capsulation loci or other genetic differences, such as pathogenicity islands, are the main determinants of the propensity of serotype III strains to cause late-onset disease. This study supports the notion that GBS strain NEM316 has four putative pathogenicity islands, but none is absolutely necessary for disease causation, whether early- or late-onset sepsis. Mobile genetic elements are a common feature of GBS isolates, with each strain having its own peculiar burden of transposons, phages, integrases and integrated plasmids. The majority of these are unlikely to influence the disease capacity of an isolate. Serotype associated disease phenotypes may thus be solely related to differences in the capsulation loci.
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Islas Genómicas/genética , Streptococcus agalactiae/clasificación , Streptococcus agalactiae/genética , Genoma Bacteriano , Serotipificación , Factores de VirulenciaRESUMEN
PURPOSE OF REVIEW: Group B streptococcus is a leading cause of neonatal pneumonia, septicaemia and meningitis. Up to one quarter of women in labour are now given intravenous antibiotics to prevent early-onset disease by the organism, a situation that will remain constant until a successful vaccine is available. From a molecular understanding of the pathogenicity of group B streptococcus we may be able to devise novel means for controlling disease, such as identifying inhibitors of key metabolic pathways or regulatory networks. This review summarizes our post-genomic knowledge of the regulation, metabolism and virulence of group B streptococcus. RECENT FINDINGS: Although advances have been made in the understanding of classic group B streptococcus virulence traits, such as capsular polysaccharide, beta-haemolysin, C5a peptidase, adhesins and immunogenic surface proteins, the major recent contribution to group B streptococcus pathogenesis has been the whole genome sequencing of three group B streptococcus strains, representing serotypes Ia, III and V. From these genomes, we not only see where the classic virulence genes map, but we can also gain insights into the metabolism and regulation of the organism and how these affect its virulence. SUMMARY: Knowledge of virulence factors and the organism's metabolism and gene regulation offers opportunities to find novel means of preventing group B streptococcus infection in babies.
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Bacteriemia/microbiología , Recién Nacido , Infecciones Estreptocócicas/microbiología , Streptococcus agalactiae/patogenicidad , Factores de Virulencia/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Humanos , Streptococcus agalactiae/genética , Virulencia , Factores de Virulencia/genéticaRESUMEN
It is a basic principle of genetics that each chromosome is transmitted from parent to offspring with a probability that is given by Mendel's laws. However, several known biological processes lead to skewed transmission probabilities among surviving offspring and, therefore, to excess genetic sharing among relatives. Examples include in utero selection against deleterious mutations, meiotic drive, and maternal-fetal incompatibility. Although these processes affect our basic understanding of inheritance, little is known about their overall impact in humans or other mammals. In this study, we examined genome screen data from 148 nuclear families, collected without reference to phenotype, to look for departures from Mendelian transmission proportions. Using single-point and multipoint linkage analysis, we detected a modest but significant genomewide shift towards excess genetic sharing among siblings (average sharing of 50.43% for the autosomes; P=.009). Our calculations indicate that many loci with skewed transmission are required to produce a genomewide shift of this magnitude. Since transmission distortion loci are subject to strong selection, this raises interesting questions about the evolutionary forces that keep them polymorphic. Finally, our results also have implications for mapping disease genes and for the genetics of fertility.
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Cromosomas Humanos/genética , Genoma Humano , Mapeo Cromosómico/métodos , Familia , Femenino , Genes Letales/genética , Genes Recesivos/genética , Genotipo , Humanos , Masculino , Núcleo Familiar , Estadísticas no ParamétricasRESUMEN
Azithromycin is highly active against Legionella pneumophila and has been shown to be efficacious in animal models and in clinical studies of patients with legionnaires disease. This open, prospective, multicenter trial evaluated azithromycin for the treatment of legionnaires disease. Twenty-five hospitalized patients with community-acquired pneumonia and a positive result of a L. pneumophila serogroup 1 urinary antigen assay received monotherapy with intravenous azithromycin (500 mg/day) for 2-7 days, followed by oral azithromycin (1500 mg administered over the course of 3 or 5 days). The mean total duration of intravenous plus oral therapy was 7.92 days. The overall cure rate among clinically evaluable patients was 95% (20 of 21 patients) at 10-14 days after therapy and 96% (22 of 23 patients) at 4-6 weeks after therapy. The results of this study support previously reported data demonstrating that azithromycin is both safe and efficacious for the treatment of hospitalized patients with legionnaires disease.
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Antibacterianos/uso terapéutico , Azitromicina/uso terapéutico , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Legionella , Enfermedad de los Legionarios/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/efectos adversos , Azitromicina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Previous studies have suggested that defective immune responses in early life may be related to the immaturity of neonatal antigen-presenting cells. To test this hypothesis, we assessed the capacity of neonatal dendritic cells (DC) to prime and polarize in vitro human naive antigen-specific T cells. We report that mature cord blood DC efficiently prime an oligoclonal population of antigen-specific CD8 T cells, capable of cytolytic activity and IFN-gamma secretion. In contrast, cells primed by immature cord blood DC do not acquire cytolytic activity and secrete lower amounts of IFN-gamma. Upon priming by either immature or mature DC, neonatal T cells acquire markers of activation and differentiation towards effector-memory cells. Our results demonstrate that, if appropriately activated, neonatal DC can prime efficient cytotoxic T lymphocyte (CTL) responses. Furthermore, these findings have important implications for the development of vaccine strategies in early life and for the reconstitution of a functional CTL repertoire after bone marrow transplantation.
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Citotoxicidad Inmunológica , Células Dendríticas/inmunología , Sangre Fetal/inmunología , Linfocitos T Citotóxicos/inmunología , Células Presentadoras de Antígenos/inmunología , Línea Celular , Sangre Fetal/citología , Humanos , Memoria Inmunológica , Recién Nacido , Interferón gamma/biosíntesis , Activación de Linfocitos , Péptidos/sangre , Péptidos/inmunologíaRESUMEN
The gene for the nicotinamide riboside (NR) transporter (pnuC) was identified in Haemophilus influenzae. A pnuC mutant had only residual NR uptake and could survive in vitro with high concentrations of NR, but could not survive in vivo. PnuC may represent a target for the development of inhibitors for preventing H. influenzae disease.
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Genes Bacterianos , Haemophilus influenzae/genética , Haemophilus influenzae/metabolismo , Mutación , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Secuencia de Bases , Transporte Biológico Activo , ADN Bacteriano/genética , Prueba de Complementación Genética , Infecciones por Haemophilus/etiología , Infecciones por Haemophilus/microbiología , Cinética , Compuestos de PiridinioRESUMEN
We investigated aerobic metabolism in Haemophilus influenzae to better understand its essential physiological growth pathways. We describe the isolation and characterization of transposon insertions leading to knockout mutations in lpdA, encoding dihydrolipoamide dehydrogenase. H. influenzae Rd lpdA::Tn10d-cat mutants were unable to grow aerobically and an H. influenzae type b lpdA::Tn10d-cat mutant was significantly attenuated in an infant rat infection model. Since LpdA is a functional subunit of both pyruvate dehydrogenase (aceEF) and alpha-ketoglutarate dehydrogenase (sucAB) the phenotype of the lpdA mutant was further explored by creating separate knockout mutants in the sucAB and aceEF loci. DeltaaceEF and deltasucAB mutants were both significantly attenuated in virulence in the infant rat, but only the sucAB mutant was able to grow aerobically. We therefore conclude that the ability for aerobic growth is critical for invasive disease, and furthermore that a TCA cycle enzyme, alpha-ketoglutarate dehydrogenase, appears to contribute a key metabolic function in vivo, but is not required for growth under laboratory conditions.