Pharmacological blockage of the AHR-CYP1A1 axis: a call for in vivo evidence.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that can be activated by structurally diverse compounds arising from the environment and the microbiota and host metabolism. Expanding evidence has been shown that the modulation of the canonical pathway of AHR occurs during several chronic diseases and that its abrogation might be of clinical interest for metabolic and inflammatory pathological processes. However, most of the evidence on the pharmacological abrogation of the AHR-CYP1A1 axis has been reported in vitro, and therefore, guidance for in vivo studies is needed. In this review, we cover the state-of-the-art of the pharmacodynamic and pharmacokinetic properties of AHR antagonists and CYP1A1 inhibitors in different in vivo rodent (mouse or rat) models of disease. This review will serve as a road map for those researchers embracing this emerging therapeutic area targeting the AHR. Moreover, it is a timely opportunity as the first AHR antagonists have recently entered the clinical stage of drug development.

In vitro and in vivo antitrypanosomatid activity of 5-nitroindazoles.

Previously, we have identified a series of 5-nitroindazoles with good antiprotozoal activities, against Trypanosoma cruzi epimastigotes and Trichomonas vaginalis. Most of them have shown very low unspecific toxicity on macrophage cell lines. In the present work, we assayed these compounds on T. cruzi bloodstream trypomastigotes and Leishmania promastigotes (Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum). Derivatives 1, 2, 7 and 8 displayed remarkable trypanocidal activity (>80% lysis) equivalent to gentian violet. Derivatives 2 and 10, as Pentamidine, caused the complete lysis of promastigotes of Leishmania. An oxidative stress-mediated mechanism of action was confirmed for derivatives 1, 10 and 12 on T. cruzi epimastigotes. Supported by the in vitro activities, derivatives 1 and 2 were submitted to in vivo assays using an acute model of Chagas' disease and a short-term treatment. None of the animals treated with derivatives 1 and 2 died, unlike the untreated control and Benznidazole groups.

Relative importance of amino acids, glycine-betaine and ectoine synthesis in the biocontrol agent Pantoea agglomerans CPA-2 in response to osmotic, acidic and heat stress.

AIMS: The objective of this work was to determine the role of different compatible solutes in adaptation of Pantoea agglomerans CPA-2 at different stages of growth to solute (0.98, 0.97, 0.96 aw), heat (35 and 40 degrees C) and acidic (pH 4.0, 5.0, 6.0) stress. METHODS AND RESULTS: Solute stress was imposed by using NaCl, glucose or glycerol, and pH was imposed with malic and citric acids. The accumulation of glycine-betaine, ectoine and amino acids in bacterial cells was quantified using high performance liquid chromathography (HPLC). There was a significant (P<0.05) accumulation of glycine-betaine (NaCl modified, 100-150 micromol g(-1) dry weight of cells) and ectoine (glucose modified media, >340 micromol g(-1) dry weight of cells) in the cells over a 48 h incubation period when compared with controls (<10 micromol g(-1) dry weight of cells). Chromatographic profile of amino acids was different with respect to control when NaCl or glucose was used as osmolyte. CONCLUSIONS: Pantoea agglomerans CPA-2 cells synthesised significant amounts of glycine-betaine and ectoine in response to imposed solute stress. However, these compounds and tested amino acids were not involved in cellular adaptation to either heat or pH stress. SIGNIFICANCE AND IMPACT OF THE STUDY: This type of information can be effectively applied to improve ecophysiological quality of cells of bacterial biocontrol agents for better survival and biocontrol efficacy in the phyllosphere of plants.

Negative cross-communication among wheat rhizosphere bacteria: effect on antibiotic production by the biological control bacterium Pseudomonas aureofaciens 30-84.

Phenazine antibiotic production in the biological control bacterium Pseudomonas aureofaciens 30-84 is regulated in part via the PhzR/PhzI N-acyl homoserine lactone (AHL) system. Previous work showed that a subpopulation of the wheat rhizosphere community positively affected phenazine gene expression in strain 30-84 via AHL signals (E. A. Pierson, D. W. Wood, J. A. Cannon, F. M. Blachere, and L. S. Pierson III, Mol. Plant-Microbe Interact. 11:1078-1084, 1998). In the present work, a second subpopulation, one that negatively affected phenazine gene expression, was identified from this rhizosphere community. Strain 30-84 grown in conditioned medium (CM) from several strains produced lower levels of phenazines (1.5- to 9.3-fold) than control when grown in CM from the strain 30-84I(1)/I(2). Growth of the phzB::lacZ reporter strain 30-84Z in this CM resulted in decreased lacZ expression (4.3- to 9.2-fold) compared to growth of the control strain in CM, indicating that inhibition of phzB occurred at the level of gene expression. Preliminary chemical and biological characterizations suggested that these signals, unlike other identified negative signals, were not extractable in ethyl acetate. Introduction of extra copies of phzR and phzI, but not phzI alone, in trans into strain 30-84Z reduced the negative effect on phzB::lacZ expression. The presence of negative-signal-producing strains in a mixture with strain 30-84 reduced strain 30-84's ability to inhibit the take-all disease pathogen in vitro. Together, the results from the previous work on the positive-signal subpopulation and the present work on the negative-signal subpopulation suggest that cross-communication among members of the rhizosphere community and strain 30-84 may control secondary metabolite production and pathogen inhibition.

Association of calnexin with wild type and mutant AVPR2 that causes nephrogenic diabetes insipidus.

Over 155 mutations within the V2 vasopressin receptor (AVPR2) gene are responsible for nephrogenic diabetes insipidus (NDI). The expression and subcellular distribution of four of these was investigated in transfected cells. These include a point mutation in the seventh transmembrane domain (S315R), a frameshift mutation in the third intracellular loop (804delG), and two nonsense mutations that code for AVPR2 truncated within the first cytoplasmic loop (W71X) and in the proximal portion of the carboxyl tail (R337X). RT-PCR revealed that mRNA was produced for all mutant receptor constructs. However, no receptor protein, as assessed by Western blot analysis, was detected for 804delG. The S315R was properly processed through the Golgi and targeted to the plasma membrane but lacked any detectable AVP binding or signaling. Thus, this mutation induces a conformational change that is compatible with endoplasmic reticulum (ER) export but dramatically affects hormone recognition. In contrast, the W71X and R337X AVPR2 were retained inside the cell as determined by immunofluorescence. Confocal microscopy revealed that they were both retained in the ER. To determine if calnexin could be involved, its interaction with the AVPR2 was assessed. Sequential coimmunoprecipitation demonstrated that calnexin associated with the precursor forms of both wild-type (WT) and mutant receptors in agreement with its general role in protein folding. Moreover, its association with the ER-retained R337X mutant was found to be longer than with the WT receptor suggesting that this molecular chaperone also plays a role in quality control and ER retention of misfolded G protein-coupled receptors.

Nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus, which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone arginine vasopressin. Polyuria, with hyposthenuria, and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital nephrogenic diabetes insipidus are males with the X-linked recessive form of the disease (OMIM 304800) who have mutations in the arginine vasopressin receptor 2 gene (AVPR2), which codes for the vasopressin V2 receptor. The gene is located in chromosomal region Xq28. In <10% of the families studied, congenital nephrogenic diabetes insipidus has an autosomal-recessive or autosomal-dominant (OMIM 222000 and 125800, respectively) mode of inheritance. Mutations have been identified in the aquaporin-2 gene (AQP2), which is located in chromosome region 12q13 and codes for the vasopressin-sensitive water channel. When studied in vitro, most AVPR2 mutations result in receptors that are trapped intracellularly and are unable to reach the plasma membrane. A few mutant receptors reach the cell surface but are unable to bind arginine vasopressin or to properly trigger an intracellular cyclic AMP signal. Similarly, aquaporin-2 mutant proteins are misrouted and cannot be expressed at the luminal membrane. Chemical or pharmacological chaperones have been found to reverse the intracellular retention of aquaporin-2 and arginine vasopressin receptor 2 mutant proteins. Because many hereditary diseases stem from the intracellular retention of otherwise functional proteins, this mechanism may offer a new therapeutic approach to the treatment of those diseases that result from errors in protein kinesis.

Pharmacological chaperones: a new twist on receptor folding.

Protein misfolding is at the root of several genetic human diseases. These diseases do not stem from mutations within the active domain of the proteins, but from mutations that disrupt their three-dimensional conformation, which leads to their intracellular retention by the quality control apparatus of the cell. Facilitating the escape of the mutant proteins from the quality control system by lowering the temperature of the cells or by adding chemicals that assist folding (chemical chaperones) can result in proteins that are fully functional despite their mutation. The discovery that ligands with pharmacological selectivity (pharmacological chaperones) can rescue the proper targeting and function of misfolded proteins, including receptors, might help to develop new treatments for 'conformational diseases'.

Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants.

Over 150 mutations within the coding sequence of the V2 vasopressin receptor (V2R) gene are known to cause nephrogenic diabetes insipidus (NDI). A large number of these mutant receptors fail to fold properly and therefore are not routed to the cell surface. Here we show that selective, nonpeptidic V2R antagonists dramatically increase cell-surface expression and rescue the function of 8 mutant NDI-V2Rs by promoting their proper folding and maturation. A cell-impermeant V2R antagonist could not mimic these effects and was unable to block the rescue mediated by a permeant agent, indicating that the nonpeptidic antagonists act intracellularly, presumably by binding to and stabilizing partially folded mutants. In addition to opening new therapeutic avenues for NDI patients, these data demonstrate that by binding to newly synthesized mutant receptors, small ligands can act as pharmacological chaperones, promoting the proper folding and maturation of receptors and their targeting to the cell surface.

Clinical Microbiology Reviews: genesis of a journal.

In 1986 planning for a new ASM review journal, Clinical Microbiology Reviews (CMR), began. CMR would publish articles primarily of interest to persons concerned with pathogenesis, laboratory diagnosis, epidemiology, and control of human and veterinary pathogens. The first issue was published in January 1988, with quarterly publication since then. The journal quickly became successful in terms of subscribers and impact on the field, earning a strong national and international reputation. The achievements of CMR are owed to many persons, including the editorial board, the production team, and especially the contributing authors.

A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation.

One of the assumptions of the mobile receptor hypothesis as it relates to G protein-coupled receptors is that the stoichiometry of receptor, G protein, and effector is 1:1:1 (Bourne, H. R., Sanders, D. A., and McCormick, F.(1990) Nature 348, 125-132). Many studies on the cooperativity of agonist binding are incompatible with this notion and have suggested that both G proteins and their associated receptors can be oligomeric. However, a clear physical demonstration that G protein-coupled receptors can indeed interact as dimers and that such interactions may have functional consequences was lacking. Here, using differential epitope tagging we demonstrate that beta2-adrenergic receptors do form SDS-resistant homodimers and that transmembrane domain VI of the receptor may represent part of an interface for receptor dimerization. The functional importance of dimerization is supported by the observation that a peptide derived from this domain that inhibits dimerization also inhibits beta-adrenergic agonist-promoted stimulation of adenylyl cyclase activity. Moreover, agonist stimulation was found to stabilize the dimeric state of the receptor, while inverse agonists favored the monomeric species, which suggests that interconversion between monomeric and dimeric forms may be important for biological activity.

Palmitoylation: a post-translational modification that regulates signalling from G-protein coupled receptors.

Protein acylation is a post-translational modification that has seized much attention in the last few years. Depending on the nature of the fatty acid added, protein acylation can take the form of palmitoylation, myristoylation, or prenylation. Palmitoylation has been implicated in the modification of several different proteins and is particularly prevalent in G-protein coupled receptors and their cognate G-proteins, where it is thought to have an important regulatory function. Given that palmitoylation of these proteins is a dynamic phenomenon in which turnover rate is modulated by agonist activation, it is thought to be implicated in processes such as receptor phosphorylation and desensitization as well as in G-protein membrane translocation. A better understanding of the regulation of signal transduction mediated by G-protein coupled receptors will require the identification and characterization of those enzymes implicated in the palmitoylation and depalmitoylation process of this large class of receptors and their signalling allies.

Transforming growth factor-beta receptor expression on endothelial cells: heterogeneity of type III receptor expression.

Recent studies of whole animal responses have defined a role for circulating TGF-beta in the preservation and stabilization of microvascular endothelial function (Lefer et al. [1993] Proc. Natl. Acad. Sci. U.S.A., 90:1018-1022; Pfister et al. [1992] J. Exp. Med., 176:265-269). In order to determine which TGF-beta receptor types are responsible for this endothelial cell responsiveness, we used an affinity-labeling technique with 125I-TGF-beta 1 and -beta 2 to characterize TGF-beta receptors on five different endothelial cell cultures: early passage bovine lung and rat epididymal fat pad microvascular endothelial cells (BLMEC and REEC), established endothelial cell lines from bovine adrenal medulla capillaries (EJG), fetal bovine heart (FBHE), and bovine pulmonary artery (CPAE). Since it is known that endothelial cells from different parts of the vasculature vary with respect to cell surface antigen expression (McCarthy et al. [1991] Trends Pharmacol. Sci., 12:462-467; Augustin et al. [1994] Bioessays, 16:901-906), it is important to compare TGF-beta receptor expression on microvascular and macrovascular endothelial cells. We observed 85 kDa and 200-400 kDa labeled receptor bands and analyzed their relationship to the cloned Type II and III receptors using peptide antibodies. We used dithiothreitol and phosphoinositol-phospholipase C pretreatments to establish whether the 65 kDa labeled band which we observed corresponded to the Type I receptor or a glycophosphotidylinositol-linked binding protein. The results demonstrated that microvascular but not macrovascular endothelial cells express high levels of the Type III receptor. This differential expression of the Type III receptor indicates that distinct anatomical segments of the vasculature have distinct TGF-beta receptor profiles. The presence of the Type III receptor on micro- but not macrovascular endothelial cells may account for the reportedly different potency of TGF-beta 1 and TGF-beta 2 on these two endothelial cell types. Analysis of the 85 kDa and 65 kDa affinity-labeled bands revealed that all the endothelial cells express the Type II receptor and a band consistent with the presence of a dithiothreitol-sensitive Type I receptor. Two isoform-specific phosphoinositol-phospholipase C releasable TGF-beta binding proteins were also detected: a 60 kDa protein on one micro- (EJG) and one macro- (FBHE) vascular endothelial cell line and a 150/180 kDa protein on the macrovascular cell lines (FBHE and CPAE). These studies emphasize the heterogeneous nature of endothelial cells and underline the importance of using microvascular endothelial cells when examining TGF-beta responses related to microvascular function.

Microflora associated with percutaneous craniofacial implants used for the retention of facial prostheses: a pilot study.

Craniofacial implants have been used successfully for the retention of facial prostheses. However, complications occur that can lead to the loss of implant integration. One such complication is infection possibly resulting from crevicular microflora activity. As part of an ongoing study, samples from crevicular sites surrounding 17 craniofacial implants were collected and submitted for microbiological assay. The results demonstrated the presence of opportunistic pathogens in many sites regardless of subjects' hygiene efforts. The significance of the findings is reviewed.

Detection of bacteremia by Difco ESP blood culture system.

In a multicenter study, the Difco ESP blood culture system (Difco Laboratories, Detroit, Mich.) was compared with the BACTEC NR660 system (Becton Dickinson Diagnostic Instrument Systems, Sparks, Md.). The ESP system monitors each blood culture bottle every 12 to 24 min to detect changes in oxygen consumption and gas production by microbes. Equal volumes of blood were inoculated into aerobic ESP-80A and BACTEC 6A, 16A, or PEDS Plus broths and anaerobic ESP-80N and BACTEC 7A or 17A broths and were incubated for up to 7 days. ESP bottles contain supplemented tryptic soy broth without antimicrobial agent-adsorbing resins. From 7,532 aerobic compliant sets, the ESP system detected 356 clinically significant positive cultures and the BACTEC NR660 system detected 329. From 6,007 anaerobic cultures, the ESP system detected 234 clinically significant positive cultures and the BACTEC NR660 system detected 198. In aerobic broths, 292 organisms were isolated from both systems and 78 organisms were isolated from the ESP system alone, whereas 54 organisms were isolated from the BACTEC NR660 system alone (P < 0.05). Among individual organisms, pneumococci were isolated significantly more often in ESP aerobic broths. In anaerobic broths, 180 organisms were isolated from both systems and 68 organisms were isolated from the ESP system alone, whereas 35 organisms were isolated from the BACTEC NR660 system alone (P < 0.05). Aerobic gram-positive organisms as a group and Candida spp. were isolated significantly more often in ESP anaerobic broths. Both systems detected 207 clinically significant bacteremic episodes and the ESP system alone detected 63, whereas the BACTEC NR660 system alone detected 32 (P < 0.05). Significantly more episodes of bacteremia caused by Staphylococcus epidermidis and anaerobes were detected by the ESP system. The differences in the numbers of organisms detected >6h earlier in ESP broths compared with BACTNEC NR660 broths were significant, as were earlier times to detection. Although the total number of organisms detected was not significantly different, the ESP system alone detected more organisms in a shorter time than did the BACTEC NR660 system alone. The continuous monitoring capability of the ESP system makes it an attractive alternative to the BACTEC NR660 system.

Multicenter clinical evaluation of a continuous monitoring blood culture system using fluorescent-sensor technology (BACTEC 9240).

The BACTEC 9240 (Becton Dickinson Diagnostic Instrument Systems, Sparks, Md.) is a new continuous-monitoring blood culture system that uses internal, fluorescent-CO2 sensors. In a multicenter clinical trial, organism yield and times to detection with the prototype BACTEC 9240 system were compared with those of the BACTEC NR 660 system. Equal volumes of blood were inoculated into the bottles included in the study blood culture sets (aerobic and anaerobic 9240 and NR6A and NR7A bottles). A total of 9,391 aerobic and 8,951 anaerobic bottle pairs were inoculated with 9,801 blood specimens. A total of 587 clinically significant positive blood cultures and 415 cases of sepsis were studied. The standard 9240 aerobic bottle detected significantly more Staphylococcus aureus (P < 0.05), coagulase-negative staphylococci (P < 0.01), and total microorganisms (P < 0.001) than the NR6A bottle. The standard 9240 anaerobic bottle detected significantly more coagulase-negative staphylococci (P < 0.001), members of the family Enterobacteriaceae (P < 0.01), and total microorganisms (P < 0.001) than the NR7A bottle. A total of 420 positive cultures were detected in both systems; for 284, the time to detection was equivalent with both systems (within 12 h); for 123, the 9240 system was faster; and for 13, the NR 660 system was faster (P < 0.001). The average times to detection for the 9240 and the NR 660 systems were 20.2 and 27.5 h, respectively. Ninety-nine cultures were positive only in the 9240 system, and 68 cultures were positive only in the NR 660 system (P < 0.02). The 9240 system also detected significantly more episodes of bacteremia (P < 0.001). The false-positive rates for the 9240 and NR 660 systems were 2.2 and 2.3%, respectively. The false-negative rates for the two systems after 5 days of incubation did not differ significantly. The contamination rates for the 9240 and NR 660 systems were 1.9 and 1.5%, respectively (P < 0.05). In conclusion, the prototype 9240 system detected more clinically significant positive blood cultures and did so sooner than the NR 660 system, with the additional advantages of full automation, continuous monitoring, and noninvasive sampling.

Diagnosis of measles by fluorescent antibody and culture of nasopharyngeal secretions.

An indirect fluorescent antibody test (IFA) was evaluated using commercial mouse anti-measles monoclonal antibody and FITC-labeled goat anti-mouse immunoglobulin. For measles isolation, specimens were inoculated into Rhesus monkey kidney (RMK) cells and, when available, CV-1 cells. 381 specimens were tested by IFA and 408 specimens were cultured from patients suspected of having measles. For the 381 specimens tested by both methods, IFA and culture were positive for 31%, culture alone for 14%, IFA alone for 15%, and both negative for 40%. This study indicates that both IFA and culture are required for maximum measles virus detection. Of the positive specimens, 48% were detected either by IFA only (24%) or culture only (24%). IFA was positive in 69% of the culture-positive specimens and therefore, provided rapid diagnosis for many patients.

Performance of a BACTEC nonradiometric medium for pediatric blood cultures.

A BACTEC aerobic nonradiometric medium, PEDS Plus, designed for diagnosis of pediatric bacteremia was evaluated in three hospital centers. Equivalent blood volumes (up to 5 ml) were inoculated into and incubated in BACTEC NR-6A (6A) and PEDS Plus broths. Among 4,581 compliant sets, 289 clinically significant organisms, representing more than 20 bacterial and two Candida species, were isolated. One hundred eighty-one isolates were recovered in both bottles, 75 in PEDS Plus only, and 33 in 6A only (P less than 0.001). Time to detection when both bottles were positive was the same for 129 isolates, detection with PEDS Plus was earlier for 39, and detection with 6A was earlier for 13 (P less than 0.005). Staphylococcus aureus was recovered significantly more often in PEDS Plus than in 6A (P less than 0.01), and more coagulase-negative staphylococci and pediatric pathogens (pneumococci, Haemophilus influenzae, and Streptococcus agalactiae) were recovered in PEDS Plus than in 6A. Coagulase-negative staphylococci and H. influenzae were detected significantly earlier in PEDS Plus (P less than 0.05 and less than 0.01, respectively). When the eight species of the family Enterobacteriaceae isolated were considered together, recovery in PEDS Plus was better than in 6A (P less than 0.05). For 66 of the 143 isolates from patients known to be on antimicrobial therapy at the time blood was drawn, PEDS Plus was superior to 6A. In 45 cases, organisms were isolated from PEDS Plus only (P less than 0.001) and in 21 cases they were isolated from PEDS Plus before 6A (P less than 0.01). PEDS Plus broth aids diagnosis of pediatric bacteremia by increasing recovery of etiologic agents and decreasing the time required for detection.

Serovars and serum resistance of Neisseria gonorrhoeae from disseminated and uncomplicated infections.

Two hundred and seventy-four gonococcal strains isolated from patients with either disseminated (DGI) or uncomplicated (UG) infection were examined to determine their serotypes/serovars by two typing systems as well as their resistance to the bactericidal action of normal human serum. The bactericidal assays were performed in particular to determine whether isolates from patients with the clinical syndrome of DGI but negative systemic cultures (suspected DGI) were serum-susceptible. When strains containing protein IA in their outer membranes and having auxotypes other than the arginine-hypoxanthine-uracil requirement were serotyped, a significant difference was found in the distribution of serovars among strains from DGI and suspected DGI compared with UG. The two typing systems revealed both antigenic similarities and differences of gonococci from Chicago and isolates from Germany reported in another study. Like DGI strains, most suspected DGI strains contained protein IA and were resistant to the bactericidal action of serum.

Direct susceptibility testing of blood culture isolates with the AutoMicrobic System (AMS).

To decrease the time needed to obtain preliminary antimicrobial susceptibility results with blood culture isolates, we inoculated a suspension of centrifuged organisms from blood culture broth directly into the AutoMicrobic System Gram-Positive (GPS) and Gram-Negative (GSC+) susceptibility cards (AMS, Vitek Systems Inc., Hazelwood, MO). Interpretive category results (susceptible, moderately susceptible, resistant) obtained by this direct method (DAMS) were then compared with results obtained by conventional inoculation (i.e., using 18-hr subcultures) of both AMS cards (CAMS method) and broth microdilution panels (MIC method, Micro-Media Systems Inc., Potomac, MD). Ninety-six Gram-positive cocci (951 antimicrobial agent--organism combinations) and 112 Gram-negative bacilli (1006 antimicrobial agent-organism combinations) were tested. When only very major (false susceptible DAMS results) and major (false resistant DAMS results) discrepancies were considered, 95% of the DAMS results for Gram-positive cocci agreed with CAMS results and 93% agreed with MIC results. Most discrepancies were observed when staphylococci were tested against oxacillin and when enterococci were tested against several antimicrobial agents. For Gram-negative bacilli, 94% of DAMS results agreed with CAMS results and 93% agreed with MIC results. Most discrepancies occurred when Enterobacter spp. and Serratia marcescens were tested against ampicillin and cefamandole. The DAMS method provides accurate and rapid preliminary susceptibility test results, usually within 6 to 7 hr of the time a positive blood culture is first detected.

Auxotypes, penicillin susceptibility, and serogroups of Neisseria gonorrhoeae from disseminated and uncomplicated infections.

We examined auxotypes, penicillin susceptibility, and outer membrane serogroups of 137 strains of Neisseria gonorrhoeae isolated from patients with disseminated gonococcal infection (DGI) and 137 control strains from patients with uncomplicated gonorrhea. We analyzed separately the data for strains isolated from systemic sites in patients with DGI and for strains from local sites in patients with the clinical syndrome of DGI (SDGI) who had negative systemic cultures. We found the nutritional requirement for arginine, hypoxanthine, and uracil (AHU auxotype) significantly more often among DGI strains than among SDGI strains. By using commercially available serogrouping reagents to detect outer membrane protein antigens, we found that regardless of strain auxotype, dissemination correlated best with the presence of protein IA antigens. We did not find that gonococci isolated from DGI are highly susceptible to penicillin. Susceptibility to low concentrations of penicillin correlated only with the AHU requirement, not with serogroup or isolation from a patient with DGI or SDGI.